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The link between chronic stress and energy homeostasis has been convincingly demonstrated in various preclinical models, clinical populations, and epidemiological studies. Psychosocial and socioeconomic challenges such as low income, low education, unemployment, and divorce have been associated with neuroendocrine- autonomic dysregulation followed by visceral obesity and associated risk factors for disease. Factors such as intensity of the stressor, duration of the exposure/recovery, potential for habituation to the stressor itself, diet, animal species, strain, and sex, are amongst the most crucial contributors to the final metabolic outcome. This chapter reviews energy balance and the concept of stress, describes in detail the rodent models of stress and highlights similarities and differences in the protocols and the resulting phenotype. It ends with an analysis of the few studies published so far that have identified a molecular mechanism of the stress-induced metabolic effects by using pharmacogenetic approaches and not only measured biomarkers of stress or metabolic functions.
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Handbook of Neurobehavioral Genetics and Phenotyping, First Edition. Edited by Valter Tucci.
© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.
Introduction
In today’s society, the complex biological machinery presiding over energy balance is facing
multiple challenges. Amongst the elements that may contribute to positive energy balance and
to the development of metabolic diseases, western diet, sedentary lifestyle, and environmental
stress can be included. The link between chronic stress and energy homeostasis has been con-
vincingly demonstrated in various preclinical models, clinical populations, and epidemiologi-
cal studies. For example the Finnish twin study has identified a group of monozygotic twins
showing divergent body mass index (BMI) and obesity around puberty (e.g., Pietilainen 2004,
2008). A follow‐up study determined that the obese co‐twin showed increased neuroendocrine
markers of stress (increased urinary cortisol and catecholamines) as well as increased emo-
tional reactivity (Marniemi 2002). Overall the obese co‐twin seems to be “more stressed” than
the lean co‐twin. In line with this finding, psychosocial and socioeconomic challenges such as
low income, low education, unemployment, and divorce have been associated with neuroendo-
crine‐autonomic dysregulation followed by visceral obesity and associated risk factors for dis-
ease (Rosmond and Bjorntorp 2000). Chronic work stress, for example, correlates with obesity
in humans and can double the risk of metabolic syndrome (Branth 2007). Recent meta‐analyses
have revealed that a plethora of emotional stressors can be found in association with increased
risk of obesity and type 2 diabetes (T2D) (Mooy 2000; Raikkonen 2007). The Whitehall II study
clearly established a link between lifetime stress exposure and the development of metabolic
syndrome (MetS) and insulin resistance (Chandola 2006). Other important studies such as the
National Health and Nutrition Examination Survey and the MacArthur Studies of Successful
Aging also clearly established a connection between individual socioeconomic status, health,
and mortality. Interestingly, the effect of (objective or subjective) socioeconomic status is par-
ticularly relevant for obesity, T2D and MetS (Mackenbach 1997; McEwen and Mirsky, 2002;
Brunner 2007). Moreover, stress has been associated to overeating in both men and women
(Van Strien 1986; Greeno and Wing 1994); notably, stress‐driven eaters typically prefer food
rich in fats and high in palatability (Laitinen 2002; Dallman 2010).
The impact of stress on metabolic function is well documented in primate models (see
Shively 2009 for review). For example, both in captivity and the wild, Cynomolgus monkeys
4
How does Stress Affect Energy Balance?
Maria Razzoli, Cheryl Cero, and Alessandro Bartolomucci
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
“This chapter was finalized and accepted for publication in April 2013. Accordingly, the literature cited does not
include papers published after the acceptance date.
Handbook of Neurobehavioral Genetics and Phenotyping
54
(Macaca fascicularis) are organized into linear social hierarchies (Sapolsky 2005, Shively 2009,
2012). Subordinate monkeys have higher basal cortisol levels and have higher heart rates in
response to challenge than dominants. Moreover, a relationship between social subordination,
fat distribution, and associated metabolic characteristics has been demonstrated (Shively2009).
Hyperglycemia and associated central fat redistribution in subordinate monkeys is reminiscent
of MetS in obese humans, linking social subordination to an overall positive energy balance
outcome (Shively 2009). Subordinate females also present evidence of glucocorticoid receptor
downregulation in central areas which modulates the hypothalamus‐pituitary‐adrenocortical
(HPA) axis response to peripheral negative feedback and promotes visceral obesity (Shively
2009). In turn the metabolic characteristics of visceral obesity (e.g., hyperinsulinemia, leptin,
free fatty acids, proinflammatory cytokines, etc.) may activate the HPA‐axis response by
enhancing sympathetic drive. It is quite likely that these responses to social stress are shared by
many primate species (Kaufman 2005; Kavanagh 2007; Wilson 2008; Arce 2010; Tardif 2009).
Similar stress‐induced behavioral, physiological, and neurochemical alterations have been
reported in subordinate tree shrews (Tupaia belangeri), a solitary species regarded as interme-
diate between insectivores and primates (Fuchs 2005). However, chronic stress in subordinate
tree shrews results in weight loss that has been attributed to stress‐induced enhancement of
metabolic activity and to a lesser extent to reduced food intake (Fuchs and Flugge 2002). This
dichotomy is not likely a species‐related effect. In fact, despite the majority of human studies
pointing to a positive effect of stress on energy balance (see above), it is also well established that
stress affects eating, metabolism, and energy balance in a bidirectional way; in humans some
subjects decrease while others increase food intake and body weight (Stone and Brownell1994;
Epel 2004; Lo Sauro 2008).
As will be detailed in the rest of the chapter, the same dichotomous effect of stress on rodent
metabolism and energy balance is well documented (see Razzoli and Bartolomucci 2016 for an
updated review). How is it possible to reconcile these opposite outcomes of stress? And what
are the underlying molecular mechanisms?
A first major challenge is due to the varying conceptualization of stress and how it is differently
applied between studies (see below). Additionally, given the procedural differences used to model
the consequences of stress, it is not surprising that the direction and the magnitude of the meta-
bolic alteration are far from being unambiguous. Factors such as intensity of the stressor, duration
of the exposure/recovery, potential for habituation to the stressor itself, diet, animal species,
strain, and sex, are amongst the most crucial contributors to the final metabolic outcome.
This chapter will attempt to answer these and related questions by focusing primarily on
rodent models of stress, where mechanistic studies are possible, and describing the advances
in molecular biology and neuro‐genetics. After a brief review of energy balance and the con-
cept of stress, we will describe in detail the rodent models of stress, their impact on metabo-
lism and energy balance, to then highlight similarities and differences in the protocols and the
resulting phenotype. The chapter ends with an analysis of the few studies published so far that
have identified a molecular mechanism of the stress‐induced metabolic effects by using phar-
macogenetic approaches and not only measured biomarkers of stress or metabolic functions.
Stress
A major difficulty in the study of stress and stress response is the varying definitions that have
been proposed and used operationally by scientists (McEwen 1998; Sapolsky 2000; Pakac and
Palkovits 2001; Koolhaas 2011). The problem of having so many different scientific and popular
definitions of stress has recently been discussed and the revised definition of stress that has been
4 How does Stress Affect Energy Balance? 55
proposed will be used in this chapter (Koolhaas 2011). The term "stress" should be restricted to
conditions where an environmental demand exceeds the natural regulatory capacity of an
organism, such as situations that include unpredictability and uncontrollability. In this view, the
physiological reactions that are a prerequisite of any behavior (challenge to homeostasis) should
not be called “stress” nor should arousal or adaptation to changing environmental conditions
within the regulatory range of a species (i.e., housing at "cold" and "hot" temperatures that are
within the regulatory range) be used as synonymous with “stress”.
Several metabolically active hormones stimulate or are involved in the physiological stress
response (e.g., Sapolsky 2000; Ulrich‐Lai and Herman 2009; Dallman 2010). The major compo-
nents of the stress response are: (i) the sympathetic nervous system (SNS) that innervates
peripheral organs where it releases norepinephrine (NE); (ii) the release of epinephrine (E) and
NE from the adrenal medulla (sympathetic adrenomedullary axis; SAM); and (iii) the HPA axis
secreted hormones. In the brain, neurons within the parvoventricular nucleus of the hypo-
thalamus (PVN) synthesize corticotrophin releasing hormone (CRH) and project to the median
eminence, releasing CRH into the anterior pituitary via the hypophyseal portal vessels to stim-
ulate production and secretion of hormones such adrenocorticotropin releasing hormone
(ACTH). In turn ACTH stimulates the adrenal cortex to secrete glucocorticoids.
Overall, while glucocorticoid might exert a pro‐adipogenic role (particularly in visceral fat),
catecholamines are largely responsible for a pro‐lipolytic role via activation of βAR (adrenergic
receptors). Therefore one of major unresolved issues in stress physiology is to identify why
under certain conditions adipogenic‐promoting or lipolytic‐promoting mechanisms will prevail.
Energy Balance and Metabolic Disorders
The physiologic regulation of the body’s metabolic function is a complex phenomenon that
relies on the communication between brain, gut, and adipose tissue. To maintain energy home-
ostasis, the brain tightly monitors the peripheral energy state on the basis of two major groups
of metabolic inputs: short term signals produced by the gut system and the autonomic nervous
system, and long term signals produced by gut adipose tissue, liver, muscle, etc. After central
integration of these inputs, the brain generates neuronal and hormonal outputs to balance
energy intake with expenditure. Miscommunication between gut, brain, and adipose tissue, or
the degradation of input signals once inside the brain may lead to increased energy intake and
production, eventually causing metabolic disorders. The efficient maintenance of the delicate
homeostatic balance of energy, glucose, and lipid metabolism largely depends on systemic met-
abolic processes that are centrally regulated. The hypothalamus is a central integrator of meta-
bolic information, with nuclei such as ventral medial hypothalamus (VMH) and arcuate nucleus
(Arc) expressing high levels of receptors for adipokines (i.e., cell signaling molecules secreted
by adipose tissue), gut and pancreatic hormones (Schwartz 2000; Yi and Tschop 2012). In the
hindbrain, the nucleus tractus solitarius (NTS) is the detector of metabolic feedback, especially
from the gastrointestinal system via vagal afferents or the circulation (Berthoud 2006). The gut
is in charge of energy intake: nutrient digestion and absorption trigger the secretion of gut
satiety signals such as cholecystokinin, peptide Y (PYY), and glucagon like peptide‐1 (GLP1)
for stimulation of vagal sensory nerves to provide feedback to the brain (Berthoud 2008; Yi and
Tschop 2012). Vagal sensory terminals also express receptors for other gut hormones and met-
abolically active peptides. Additionally, gut hormones and nutrients can have central effects
acting on circumventricular organs (Cottrell and Ferguson 2004). These brain areas then relay
the information to other key regulatory areas, such as the PVN (to maintain systemic metabolic
homeostasis by modulating neuroendocrine and autonomic outputs) and the suprachiasmatic
Handbook of Neurobehavioral Genetics and Phenotyping
56
nucleus (SCN) (to synchronize the behavior and physiology of the autonomic outflow).
Malfunctioning at the central level can result in abnormal elevation of sympathetic outflow. On
the other hand, defective or weakened signal feedback by the brain in response to satiety and
nutrients from the gut can cause overfeeding and disinhibition of liver glucose production, and
thereby promote metabolic disease (Berthoud 2002). The fact that stress can lead to under‐ and
over‐eating exemplifies the “stress‐eating paradox” (Connor 1999; Serlachius 2007; Coccurello
2009). Highly palatable food has properties that promote dependence; palatable food can in
fact activate the brain reward system, comprising opioid, dopamine, and endocannabinoid,
acting via both fast sensory inputs as well as slower post‐ingestive processes, such as increased
blood glucose, adiposity, and possibly gut signals (Coccurello 2009; Dallman 2010). Repeated
stimulation of the central reward pathways through highly palatable food may lead to neuro-
biological adaptations that eventually increase the compulsive nature of overeating character-
ized by the frequent drive to initiate eating (Coccurello 2009). It must be noted that the
activation of the HPA axis elicits– among other neurotransmitter systems –the release of
endogenous opioids. Opioids decrease activity of the HPA axis on different levels. Opioid
release increases palatable food intake and palatable food sustains opioid release (see Cota
2006 for a review on food and reward). Consumption of palatable foods clearly reduces CRH
mRNA expression in the PVN, the central drive of HPA axis activation (Pecoraro 2004).
Similarly, daily limited access to sucrose or saccharin solutions also results in reduced PVN
CRH mRNA expression (Ulrich‐Lai 2007).
Obesity can be defined as excessive body weight and adiposity to such an extent as to dam-
age health, increasing the likelihood of life threatening conditions such as hypertension,
stroke, T2D, cardiovascular disease, and cancer (Danaei 2009). Adipose depot size is a result
of the balance between actions that promote lipid accumulation and those that promote lipol-
ysis (Thompson 2010; Cinti 2012). Energy balance is also dependent upon signals to the brain
from the white adipose tissue via sensory nerves (Bartness 2010; Murphy 2013). Adipose tis-
sue produces adipokines that inform the brain about whole‐body long term energy storage
status and drive the brain’s control of energy balance and the long term regulation of body
weight. To date, several adipokines have been identified. Leptin is sensed by the central nerv-
ous system (CNS) and sensory neurons in the white adipose tissue for feeding and energy
expenditure regulation (Halaas 1995; Maffei 1995; Murphy 2013). Central leptin resistance is
caused by defective leptin sensing in these brain regions (Gautron and Elmquist 2011).
Generally, leptin resistance can lead to misinterpretation of long‐term energy stores and, as a
result, catabolic pathways are not appropriately activated to compensate for excessive nutri-
ents. The dominant autonomic–white adipose tissue connections are postganglionic sympa-
thetic nerves that initiate lipid mobilization in white adipose tissue largely via NE secretion
(Foster 2010). Loss of autonomic control from the PVN can increase the accumulation of
lipids in fat depots without influencing lipid mobilization, suggesting that obesity could be
caused by excess energy deposition owing to malfunction of the sympathetic autonomic nerv-
ous system. Uncoupling protein 1 (UCP1) is a mitochondrial protein mainly expressed in
brown adipose tissue with the primary function of dissipating chemical energy to form heat
through the process of non‐shivering thermogenesis (Cannon and Nedergaard 2004). The
activation of UCP1 by NE and subsequent signaling cAMP‐PKA‐p38 pathway has been well
established and leads to increase of energy expenditure that is crucial to the regulation of
whole body energy and metabolism (Cannon and Nedergaard 2004; Collins 2004). The UCP1
gene is regulated by the sympathetic nervous system and its transcription is stimulated by NE
released from sympathetic nerves innervating brown adipose tissue; this induces the increase
in heat production and therefore increases energy expenditure as seen in response to cold
exposure (Cassard‐Doulcier 1993; Lowell and Bachman 2003).
4 How does Stress Affect Energy Balance? 57
Pro‐adipogenic Stress Mediators
In the fasted state, cortisol stimulates several processes that collectively serve to increase and
maintain normal concentrations of glucose in the blood (Sapolsky 2000). Unremitting stress
may result in chronic hyperactivation of the HPA axis and sustained glucocorticoid produc-
tion. The long term effects of glucocorticoids on adipocyte metabolic processes are thought to
promote visceral obesity (Bjorntorp 2001; Black 2006). The binding of glucocorticoids to the
glucocorticoid receptors (GR) induces the expression of lipoprotein lipase (LPL). LPL pro-
motes fatty acid uptake and storage as triglycerides in fat, promoting visceral fat accumulation.
Furthermore, the stromal cells in visceral fat contain relatively high levels of the enzyme 11β
hydroxy‐steroid dehydrogenase type 1 (11β‐HSD1), which converts inactive cortisone to the
active cortisol, thus enhancing the downstream effects of glucocorticoids, again facilitating
visceral fat accumulation (Lundgren 2008). Furthermore, it has been demonstrated that in the
presence of the anti‐lipolytic hormone insulin, glucocorticoids increase craving for calorie‐rich
meals and that this may lead to a metabolic derangement leading to increased abdominal fat
(Rebuffé‐Scrive 1992; Pecoraro 2004; Dallman 2003, 2004; la Fleur 2004). Beside glucocorti-
coids and insulin, other stress mediators have a pro‐adipogenic role. Obesity, particularly vis-
ceral obesity, is now recognized as a systemic low‐grade inflammatory state (Hotamisligil 1993;
Chawla 2011). These fat borne proinflammatory cytokines sustain a hypersecretory HPA axis,
which in turn promotes visceral fat accumulation. Thus the relationship between stress and
visceral obesity may be bidirectional and self‐sustaining (Black 2006; Kyrou and Tsigos 2007;
Beasley 2009). Finally, sympathetic‐derived neuropeptide Y (NPY) induces a pro‐adipogenic
and pro‐angiogenic programming under specific stress conditions and in the presence of a high
fat diet by binding Y2 receptor (Y2R) in adipocyte membranes (results discussed in detail
below) (Kuo 2007, 2008).
Pro‐lipolytic Effect ofStress Mediators
Catecholamines are the major pro‐lipolytic and thermogenic factors in mammals via activa-
tion of β adrenergic receptors (βARs) (Lowell and Spiegelman 2000; Bachman 2002). The
genetic ablation of the three known βARs in the so called β‐less mice led to morphological
abnormalities in the brown adipose tissue, defective adaptive thermogenesis, obesity, and glu-
cose intolerance (Bachman 2002; Asensio 2005). In addition other mediators released under
certain stress conditions such as TSH and T3/T4, nutrietic peptides, granins, and many others
have been shown to increase lipolysis (e.g., Liu and Brent 2010; Bordicchia 2012). Overall,
increased and sustained lipolysis and increased circulating free fatty acids can in turn pro-
mote glucose intolerance, hyperinsulinemia, and dyslipidemia by influencing hepatic function
(Arner 1997) if this is not compensated by an equivalent increase in nutrient metabolism and
energy expenditure.
How does Stress Affect Energy Balance?
Simply stated, energy homeostasis reflects the balance between energy input to the system
(nutrients) and the energy output (energy expenditure divided into obligatory and adaptive
thermogenesis) (Lowell and Spiegelman 2000). A negative energy balance, defined as loss of
body weight or fat mass, can occur in the presence of decreased food intake and/or increased
energy expenditure. Vice versa, a positive energy balance can occur in the presence of increase
food intake and unchanged or reduced energy expenditure. Because of the physiological sys-
tems evolved to maintain a strict control over energy balance, a sustained weight loss or weight
Handbook of Neurobehavioral Genetics and Phenotyping
58
gain usually leads to compensatory responses in the opposite direction. Alternatively, in an
allostatic (non‐homeostatic) perspective (McEwen 1998), the system might adapt to a different
set‐point which maintains stability through changes.
In an attempt to shed light on the mechanisms of stress‐induced metabolic disorders we will
discuss animal models of stress‐induced metabolic disorders using an energy balance perspec-
tive and a two‐tier classification. The first tier is the nature of stress: social or non‐social (physi-
cal, psychological) stress models. The second tier is the net positive/negative energy balance (as
measured from pre‐stress condition and, in rare instances, compared to controls): positive bal-
ance is defined as increased body weight or fat mass; negative balance is defined as loss of
weight or fat mass (Tables 4.1 and 4.2). For each model we will describe first changes in food
intake and energy expenditure and then we will summarize changes in neuroendocrine (e.g.,
HPA‐axis produced hormones) or biochemical (e.g., insulin, leptin, glucose, etc.) markers. The
metabolic effect of “recovery” after stress and its molecular mechanisms will be discussed in
separate sections.
With regard to the nature of the stress, laboratory stressors can be broadly defined as social
or physical/psychological (non‐social). Many experimental stressors have an acute psychologi-
cal stress aspect but are primarily physical in nature. Since the likelihood for animals (and
humans) to encounter stressors such as restraint, immobilization, or foot shock in nature is
very low, these models cannot be considered ethologically relevant. They may trigger different
coping responses such as behavioral, physiological, or neurochemical, with limited validity to
natural and ethologically relevant conditions (Bartolomucci 2007; Koolhaas 2011). Nevertheless ,
the studies based on non‐social stressors have offered insights into the biology of the stress
responses and can be considered valid experimental tools to address human coping responses
to traumatic events such as natural disasters (Tamashiro 2004).
A shared feature of all models reviewed in this chapter is that the stressors, whatever their
nature, are applied over time (i.e., chronically, repeatedly, intermittently). Acute stress models
will not be discussed because of their uncertain effect on long term energy balance.
Animal Models of Chronic Stress and their Impact on Energy
Balance
Physical andPsychological (non‐social) Chronic Stress Models
Mild Chronic Pain Models–Mild Tail Pinch, Foot Shock
Following the observations of Antelman and colleagues that mild tail pinch could reliably induce
a syndrome of gnawing and eating behavior in rats, mild pain has been proposed as a tool to pro-
duce hyperphagia (Antelman and Szechtman 1975; Rowland and Antelman 1976). Most studies
have addressed the short term mechanisms responsible for the acute hyperphagic response
(Rowland and Antelman 1976; Robbins 1977; Nemeroff 1978; Morley and Levine1980a,b). The
only study describing a long term effect of chronic application of this stressor showed an overall
negative energy balance, a decrease in body weight gain with unaffected food intake (Levine
andMorley 1981).
The mild chronic pain model based on electric foot shock is often associated with caloric
restriction (although only results obtained in ad libitum fed animals are included in this review)
(Artiga 2007; Fu 2010; Ortolani 2011). This model has validity for human eating behavior dis-
orders, primarily binge eating. Similarly to tail pinch, mild chronic pain induces a body weight
loss without any change in food intake. Nevertheless, in combination with a high‐fat and high‐
sucrose diet, it can produce a synergistic effect, aggravating insulin resistance associated with
4 How does Stress Affect Energy Balance? 59
Table 4.1 Stress‐induced negative energy balance. Models, biomarkers andmechanisms.
Model
Body
weight/ fat
Food
intake
Energy out (EE,
locomotion, body T )
Stress/neuroendocrine
biomarker Mechanism
Recovery/
maintenance Comment References
non social‐stress based models
Foot shock na cort; = BF, cholesterol, TGs rat, Wistar Fu 2010
== locomotion glucose, insulin, cort; =
leptin; TG
rat, Wistar Ortolani 2011
Tail pinch ↓ ↓ BW; =
food intake
rat,
Sprague‐Dawley
Levine and
Morley 1981
Heat ↓ ↓ leptin, adiponectin, insulin; =
FFA; glucose
mouse,
C57BL/6J
Morera 2012
Chronic Mild
Stress Models
na = cort; leptin, insulin, glucose,
adrenal, thymus, ACTH
rat,
Sprague‐Dawley
Solomon 2010
= = heart rate = adrenal, cort; BF, body lean,
leptin, insulin, glucose, thymus
rat,
Sprague‐Dawley
Flak 2011
= BF; = leptin, E, cort; NE rat, Sprague‐Dawley Levin 2000
= glucose, cort; = insulin,
adiponectin, leptin; BF,
cholesterol, TG, MCP1
rat, Wistar Paternain 2011
= = glucose, cort, ACTH;
cort, GLP‐1
GLP1 rat,
Sprague‐Dawley
Tauchi 2008
na cort; = glucose; insulin rat, Wistar Zardooz 2006
na ↓ ↑ glucose; FFA rat, Sprague‐Dawley Li 2010
na glucose; insulin rat Lin 2005
= = respiratory
efficiency ratio
body lean, resistin; = BF,
glycerol, insulin, leptin, cort;
adiponectin, glucose, FFA
mouse,
C57BL/6J
Castaneda 2011
na BF; = insulin, glucose, cort mouse, C57BL/6J, AJ Michel 2005
(Continued)
Handbook of Neurobehavioral Genetics and Phenotyping
60
Table 4.1 (Continued)
Model
Body
weight/ fat
Food
intake
Energy out (EE,
locomotion, body T )
Stress/neuroendocrine
biomarker Mechanism
Recovery/
maintenance Comment References
glucose; = body fat, lepin mouse, C57BL/6:129J Teegarden and
Bale 2008
==glucose, insulin, adrenals,
cort; BF, leptin
rat, Long Evans, female Solomon 2011
Restraint stress ↓ ↓ energy
expenditure
cort; BF, leptin, FFA, glucose rat, Wistar Harris
2002, 2006
= = cholesterol, TG, glucose,
leptin, insulin
rat, Wistar Fachin 2008
na leptin, resistin, glucose,
cholesterol, cort; TG
mouse, BalbC, female Depke 2008
na = glucose, cort, insulin rat, Wistar Zardooz 2006
↓ ↑ = cort, ACTH rat, Sprague‐Dawley Pecoraro 2004
= na adrenal; = BF, leptin, glucose,
TG, cholesterol, cort
rat, Wistar Macedo 2012
social stress‐based models
Social isolation ↓ ↓ adrenal hamster, syrian, female Meisel 1990
↓ ↓ =cort; = NE mouse, CD1, wt Yamada 2000;
Bartolomucci
2004, 2009
Sensory contact/
chronic
social defeat
na temperature; =
locomotion
cort mouse, C57BL/6J Krishnan 2007
na BF, cholesterol, HDL, cort; =
LDL; adrenal
mouse, C57BL/6J Rodriguez‐
Sureda 2007
↓ ↓ orexin mouse, C57BL/6J Orexin ‐/‐ Lutter 2008a
=ghrelin GHSR mouse, C57BL/6J GH SR‐/‐ lutter 2008b
↓ ↑ beta3
adrenergic
receptor
BW;
BF, leptin
mouse, C57BL/6J Chuang 2010b
4 How does Stress Affect Energy Balance? 61
Table 4.1 (Continued)
Model
Body
weight/ fat
Food
intake
Energy out (EE,
locomotion, body T )
Stress/neuroendocrine
biomarker Mechanism
Recovery/
maintenance Comment References
= na BF, cort;
cholesterol; =
NEFAs, glucose,
insulin
mouse, C57BL/6J Chuang 2010a
= acyl‐ghrelin; = BF,
leptin; cort
5HT2C
receptors
fluoxetine tretament,
mouse, C57BL/6J
Kumar 2013
na na Ghrelin, GHSR BW, food
intake, BF,
leptin,
acyl‐
ghrelin, cort
mouse, C57BL/6J Chuang 2011
Unstable social
settings
na adrenals, cort; = ACTH;
thymus
mouse, C57BL/6J Reber 2006
= locomotion BL; = cort; leptin,
insulin, BF
mouse, C57BL/6J Finger 2011
Visible
burrow system
↓ ↓ locomotion BF, body lean, leptin, insulin,
thymus; = adrenals; cort
amylin body weight,
food intake, fat
and lean mass;
=
corticosterone;
leptin
rat, Long Evans Tamashiro 2004,
2007a, b;
Nguyen 2007;
Melhorn 2010;
Blanchard 1995;
Smeltzer 2012
Chronic
psychosocial
stress
(dominant)
↓ ↑ energy
expenditureand
locomotion
cort; WAT NE, BF; =
glucose, TG, FFA, leptin,
adiponectin, cholesterol
bw; food
intake; cort; =
glucose,
TG, FFA
mouse, CD1, NMRI Bartolomucci
2004, 2009;
Sanghez 2013;
Moles 2006
na, not applicable; BW, body weight; BF, body fat; BL, body lean; NE, norepinephrine; E, epinephrine; cort, corticosterone; TG, triglycerides; FFA, free fatty acids; ACTH,
adrenocorticotropic hormone; NPY, neuropeptide Y; Y2R, Y2 receptors; GHSR, growth hormone secretagogue receptor; 5HT, 5‐hydroxytryptamine; GTT, glucose tolerance test; GLP1,
glucagon‐like peptide‐1. Unless otherwise stated subjects are males.
Handbook of Neurobehavioral Genetics and Phenotyping
62
Table 4.2 Stress‐induced positive energy balance. Models, biomarkers andmechanisms.
Model
Body
weight/ fat
Energy in
(food intake)
Energy out (EE,
locomotion, body T)
Stress/neuroendocrine
biomarkers Mechanism
Recovery/
maintenance Comment Reference
non social‐stress based models
Intermittent cold = BF; =NE; E NPY, Y2R mouse,
C57BL/6J,
129X1/SvJ
Kuo 2007
Chronic mixed
stress
= na mesenteric fat pad, cort; =
glucose, insulin, TG
rat,
Sprague‐Dawley
Rebuffe’‐
Scrive 1992
social stress‐based models
Social isolation ↑ ↑ locomotion BF, TGs, FFAs, cort; =
leptin, insulin; adiponectin
mouse,
C57BL/6J
Sakakibar 2012
= = locomotion = cort mouse, ICR Kabuki 2009
↑ ↑ rat, Wistar Scalera 1992
↑ ↑ rat, Listar
Hooded, female
Sahakian 1982
BW, BF and FI at HFD only.
Low BW at STD. cort, =
WAT N E.
mouse, CD1 Bartolomucci
2009
Repeated resident/
intruder test
na BF; = NE, cort; E NPY, Y2R mouse,
C57BL/6J &
129X1/Sv
Kuo 2007
↑ ↑ BF, leptin, adrenal NE; =
insulin, cort, thymus
Syrian hamster Solomon 200;
Forster 20066
Chronic
psychosocial stress
↑ ↑ temperature 1
week; locomotion;
’= energy
expenditure
cort; = WAT NE, TG, FFA,
Leptin adiponectinat,
acyl‐ghrelin, STD; BF, Chol,
TG, FFA, Leptin, insulin,
adiponectin; Glucose
intolerance
5HTT,
GHSR
vs stress
phase = vs
control group
BW, food
intake; =
acyl‐ghrelin
mouse, CD1,
C57BL6J,
129SvEV
Bartolomucci
2004, 2009,
2010; Dadomo
2011; Sanghez
2013;
Patterson 2013
4 How does Stress Affect Energy Balance? 63
Table 4.2 (Continued)
Model
Body
weight/ fat
Energy in
(food intake)
Energy out (EE,
locomotion, body T)
Stress/neuroendocrine
biomarkers Mechanism
Recovery/
maintenance Comment Reference
= energy expenditure,
locomotion
TGs, NEFAs BW,
food intake
mouse, NMRI Moles 2006
Sensory contact = = cort glucose (GTT),
insulin, HOMA‐IR, leptin
orexin mouse,
C57BL/6J
Tsuneki 2013
Unstable social
settings
= = BF; = glucose, cort mouse, CD1 Schmidt 2009
Legend: BW, body weight; BF, body fat; BL, body lean; NE, norepinephrine; E, epinephrine; cort, corticosterone; TG, triglicerydes; FFA, free fatty acids; ACTH,
adrenocorticotropic hormone; NPY, neuropeptide Y, Y2R, Y2 receptors; GHSR, growth hormone secretagogue receptor; 5HT, 5‐hydroxytryptamine; GTT, glucose tolerance
test; GLP1, glucagon‐like peptide‐1. Unless otherwise stated subjects are males.
Handbook of Neurobehavioral Genetics and Phenotyping
64
the elevation of serum free fatty acids and the activation of the HPA axis. Other consequences
of this procedure are increased TNF‐α in the serum and adipose tissue, decreased density of
high‐affinity receptors and expression of PPARα mRNA in hepatocytes, as well as nonalcoholic
fatty liver disease, considered to belong to the hepatic manifestations of MetS (Fu 2009, 2010).
Thermal Models–Cold andHeat Stress
Housing mice at temperatures lower than the standard housing in the laboratory induces
increased food intake and thermogenesis and decrease in weight and fat mass (e.g., Lowell and
Spiegelman 2002; Cannon and Nedergaard 2004; Ukropec 2006; Ochi 2008; Zhao 2010). Mice
commonly perceive housing temperatures ~21 °C as cold, given that the mouse thermoneutral
zone is at 27–30 °C). Indeed, cold stimulates the expression of thermoregulatory genes in both
brown and white adipose tissue (Trayhurn 1995; Cinti 2002). After chronic cold exposure the
brown adipose tissue is hypertrophic and presents increased UCP1 mRNA and protein levels
(Cinti 2002). Intuitively, cold increases caloric intake to match the increased energetic demand
targeting a sustainable homeothermic state; at the same time the cold challenge increases cor-
ticosterone levels, and in rats it has been associated to an overall negative energy balance and
to a thermogenic switch (Akana 1999). However, based on our definition of stress (see above),
exposure to a different ambient temperature within the regulatory range of a species should be
considered an adaptive response to a challenge to homeostasis and not a stressor. A more sub-
tle and intermittent cold stress model was developed by Kuo etal. by exposing mice daily to ice
cold water for several weeks (Kuo 2007). Under these conditions, mice developed increased
visceral fat mass without any change in body weight and food intake while energy expenditure
was not assessed (Kuo 2007). Other studies demonstrated increased inflammation, hyperlipi-
demia, increased levels of ACTH, hepatic steatosis, and atherosclerosis (Kuo 2007; Li 2011;
Han 2012; Najafi 2013). Most of these metabolic alterations are considered to be linked to a
stress‐induced facilitated release of NPY and expression of Y2R in visceral fat (Kuo 2008). As
will be discussed later on, NPY is an adrenergic cotransmitter and a major stress mediator,
preferentially released from the sympathetic nerves by intense and prolonged stressors
(Zukowska‐Grojec 1995).
At the opposite end of the thermal spectrum, chronic heat treatment is a well‐known physi-
cal stressor (Bhusaria 2008). Experimental models of chronic heat stress (mice housed above
thermoneutrality, i.e., ~35 °C) are associated to negative energy balance due to decreased body
weight and food consumption, and increased water intake and rectal temperature (Morera
2012). At the hormonal level heat treatment significantly increases both leptin and adiponectin
secretion, as well as their receptors, and up‐regulates insulin receptor substrate‐1 and glucose
transporter mRNAs (Morera 2012). Nevertheless the molecular mechanisms by which heat
stress regulates the expression and secretion of adipokines remain largely unknown, although
these changes could be considered an acclimatization of homeothermic animals to heat, i.e., a
way to increase avenues of heat loss and reduce heat production in an attempt to remain
euthermic.
Chronic Mild Stress Models: Chronic Mild Stress, Chronic Variable Stress, etc.
Chronic mild stress was developed to decrease responsiveness to rewards through a variety of
behavioral paradigms with the ultimate goal of modeling crucial symptoms of human depres-
sion. According to Willner (1997), the designation of the procedure as chronic mild stress indi-
cates: (i) that the behavioral changes induced may be observed over a period of several weeks
of continuous stress administration; (ii) that habituation either does not occur, or occurs to
only a limited extent; and (iii) that the individual stressors used do not include any of the
severely stressful elements such as intense foot shock, prolonged food/water deprivation, etc.
4 How does Stress Affect Energy Balance? 65
Based on this concept, several procedures based on the chronic application of different mild
intensity stressors have been developed and referred to quite interchangeably as chronic mild
or variable stress. Notwithstanding the lack of standardization in the application of these pro-
cedures, they will be treated together for the purposes of the present discussion and will be
referred to as chronic mild stress. In a typical experiment, rats or mice are exposed sequentially
to a variety of mild stressors (e.g., overnight illumination; periods of food and/or water depriva-
tion; cage tilt; change of cage mate), which change every few hours over a period of weeks or
months (Willner 1987, 1992; Monleon 1994). Chronic mild stress induces lasting effects on
HPA axis regulation and future response to stress (Jankord and Herman 2008; Flak 2009;
Ostrander 2009). From a metabolic standpoint, chronic mild stress establishes a negative
energy balance, mainly including reduced food intake, body weight gain, and adiposity (Levin
2000; Li 2010; Solomon 2010; Flak 2011; Paternain 2011). The only exception is a study where
rats were exposed to restraint and cage rotations on alternate days. In this case, without any
effect on fat mass and body weight (food intake and energy expenditure were not assessed)
there was an increase in mesenteric fat pad weight associated with high corticosterone (Rebuffé‐
Scrive 1992). Studies associating chronic mild stress with a high‐fat diet have shown profound
metabolic alterations both in rats and in mice suggesting that prior stress exposure has long
term consequences for metabolic regulation (Lin 2005; Teegarden and Bale 2008; Li 2010;
Zheng 2010; Castañeda 2011; Manting 2011). When obesity‐prone (C57BL/6J) and obesity‐
resistant (AJ) mice are subjected to chronic mild stress and a high‐fat diet, the chronic stress is
more catabolic than anabolic even when genes and environment are propitious to obesity
(Michel 2005). Similar effects are induced by this stressor in males and females (Fachin 2008;
Solomon 2011). Chronic mild stress is associated to high plasma corticosterone and low leptin
levels (Lu 2006). In mice fed a high‐fat diet, chronic mild stress induces lower plasma adi-
ponectin, free fatty acids, and glycerol paralleled by a lower glucose tolerance and decreased
white adipose tissue insulin sensitivity, increased lipogenesis, adipogenesis, and adipocyte dif-
ferentiation, and elevations of plasma resistin levels (Castañeda 2011).
Restraint or Immobilization
Restraint or immobilization stress models have been used extensively to study stress‐related
biological, biochemical, and physiological responses in animals (Kvetnasky and Mikulai 1970;
Marty 1997; Kasuga 1999; Bhatia 2011). Originally developed to induce classic signs of stress
(i.e., adrenal hypertrophy and thymic involution) (Selye 1956), nowadays it is the more com-
monly employed model for the induction of acute stress and for studying stress‐induced neu-
rodegeneration and post‐traumatic disorders (Southwick 1994; Kumari 2007). Restraint stress
is induced by placing rats and mice in restrainers for different durations and with different
schedules (once/twice day) over a number of days (consecutive or not) (Marin 2007; Kaur 2010;
Manchanda 2011). Only multiple exposures to this stressor will be discussed in this chapter.
Restraint stress is able to induce an overall negative energy balance, causing weight loss and
metabolic alterations that might persist following the restoration of HPA alterations
(Harris2002; Zardooz 2006; Sweis 2013). The hypermetabolic syndrome caused by restraint
stress exposure appears to be triggered by transiently increased energy expenditure and
reduced food intake, both of which normalize at different rates depending on the severity of the
stress induced neuroendocrine dysregulation and also on species, sex, strain, and duration and
time of stress application (Depke 2008). Habituation can occur during chronic restraint proto-
cols, as most of the components of the HPA axis appear to normalize (Harris 2002, 2006;
Pecoraro 2004; Zardooz 2006; Depke 2008; Macedo 2012). The decreased body weight is con-
current with an initial increase in corticosterone and decrease in leptin levels (Zardooz 2006;
Macedo 2012). Corticosterone levels are later normalized with a parallel change of plasma
Handbook of Neurobehavioral Genetics and Phenotyping
66
glucose fasting levels; however these changes are not necessarily mimicked by insulin, the lev-
els of which can remain decreased (Zardooz 2006). Restraint stress administered with a calo-
rie‐dense diet is associated with a blunted HPA response due to a reduction of hypothalamic
mRNA expression and secretion of CRH and ACTH in the presence of increased glucose and
insulin levels (Pecoraro 2004). Despite a reduction of total caloric intake due to restraint stress,
rats exposed to a choice between chow and palatable diet show increased consumption of the
“comfort food”. Nevertheless, when compared to unrestrained rats, rats exposed to restraint
stress show a negative food efficiency that can only partially be reversed by comfort food.
Finally and importantly, the fat mass of control and stressed rats ingesting the comfort food is
indistinguishable from and higher, respectively, than the adipose mass of rats fed a standard
chow, whether exposed or not to restraint stress (Pecoraro 2004).
Chronic Social Stress Models
Experimental models of social stress offer the best ethological approximation to the social fac-
tors that characterize animal natural life, as well as to human stressogenic situations (Sapolsk y2005;
Bartolomucci 2005; Koolhaas 2011). Intuitively the relevance of experimentally manipulating
social dynamics (social hierarchy formation, social group stability, social group size, etc.) may
be more or less adequate depending on the extent to which the animals studied live in social
groups or in close proximity to members of either their own or different species. Similarly to
non‐human primates discussed in the introduction, social factors are also commonly used as
stressful interventions on laboratory rodents.
Social Isolation, Individual Housing
The physiological and behavioral syndrome elicited by social isolation has been classically con-
sidered a model of stress‐related pathologies (Valzelli 1973). Social isolation has been widely
described as inducing numerous behavioral and neurochemical changes linked to HPA dys-
regulation, emotionality, and hypertension, although the nature and severity of these effects
depend on age at isolation, species and strain, and spe cific testing conditions (Bartolomucci2003;
Nonogaki 2007). Traditionally the effects of social isolation upon food intake and body weight
have been investigated using two different approaches (Yamada 2000). In isolation rearing,
isolation begins at weaning and body weight of isolated animals is found to be greater than that
of socially reared controls, especially in rats (Morgan and Einon 1975; Fiala 1977). Individual
housing at a post‐weaning age generally leads to decreased body weight gain and food intake
than group‐housed mice fed standard diet (Zaionc 1965; Goodrick 1974; Meisel 1990; Yamada
2000; Kabuki 2009; Bartolomucci 2003, 2009), although contrasting findings have also been
reported (Sakakibara 2012). However, when individually housed mice are fed a high‐fat diet
they can show a paradoxical positive energy balance with increased body weight, fat mass, and
food intake (Bartolomucci 2009). Rats mainly react to social isolation with an overall positive
energy balance, increasing their body weight and food intake (Morgan and Einon 1975; Fiala
1977; Sahakian 1982; Scalera 1992). In general, individual housing is not associated with
marked activation of the HPA axis unless mice are exposed to a heterotypical stressor, e.g.,
open field or restraint, in which case they show increased HPA activation when compared to
group‐housed counterparts (see discussion in Bartolomucci 2003, 2009).
Unstable Social Settings
We group here a heterogeneous category of animal models that includes procedures based on
the alternate application of social defeat/overcrowding/isolation/group composition change/
etc. Particularly interesting from this perspective are the studies on Syrian hamsters. Syrian
4 How does Stress Affect Energy Balance? 67
hamsters are naturally solitary and highly territorial (Murphy 1977). For these species group
housing represents a social stressor with an overall anabolic outcome (Borer 1988; Meisel 1990;
Fritzsche 2000). Group‐housed female Syrian hamsters increase their food intake, body and
lipid mass compared with singly housed hamsters (Borer 1988; Meisel 1990; Fritzsche 2000).
Exacerbating the group housing stress through social crowding aggravates the deposition of
excessive fat mass and the diminution of energy expenditure with consequent increase of body
weight (Borer 1988; Meisel 1990). On the contrary, in mice the alternation of social defeat and
overcrowding leads to a negative energy balance (Reber 2006). Independently from the diet
available, in this procedure mice decrease body weight and food intake, in parallel with decrease
of body fat and circulating leptin and increase in lean mass (Finger 2011). The availability of a
high‐fat diet contributes only to the amelioration of the behavioral sequelae of the social defeat/
overcrowding procedure, with no impact on any of the metabolic parameters assessed.
Furthermore, in the context of unstable social settings a shift in food choice from healthier
tocalorie‐rich foods is observed without a notable effect on energy balance (Adam and Epel
2007;Macht 2008).
Visible Burrow System
The visible burrow system is a paradigm used to study dominance hierarchies in laboratory set-
tings. Typically rats are housed in mixed‐sex groups in a seminatural social environment con-
sisting of tunnels and chambers. A male rat will become dominant, while the others will be
subordinate; once formed, the hierarchy remains stable with subordinate rats not habituating to
the stress of social subordination (Blanchard 1995; McKittrick 2000; Hardy 2002; Nguyen2007;
Tamashiro 2007a,b). The visible burrow system also elicits diverging metabolic phenotypes in
dominant and subordinate animals. Subordinate male rats consistently lose 10–15% of their
original body weight, whereas dominant males maintain their body weight. The weight loss in
subordinates is attributed to loss of adipose and lean tissue. In contrast, dominant rats maintain
their weight, but alter their body composition by losing adipose tissue and gaining lean body
mass. Both dominant and subordinate rats are hypophagic while the dominance hierarchy is
forming. Once the hierarchy is established, food intake of subordinate rats remains low whereas
that of dominant rats returns to normal and this pattern persists for the remainder of the visible
burrow system housing. The observed altered meal patterns suggest that signals normally con-
trolling ingestive behaviors become impaired or overridden during social stress. In line with this
phenotype, subordinate rats develop lower leptin and insulin levels in the presence of high levels
of corticosterone and low levels of testosterone, while dominant rats differ from control rats
only in their lower leptin levels (Tamashiro 2004, 2007a).
Intermittent Social Defeat (Resident/Intruder Procedure)
The resident/intruder procedure was developed manipulating rodent territorial disparity, by
allowing brief confrontations between a resident and an intruder subject to study mechanisms
that may contribute to affective and neuroendocrine disorders (Ginsburg and Allee 1942; Miczek
and Tornatzky 1996). After displaying defeat, the intruder is protected from the potential injury
of the resident’s attack and returned to his home cage. Repetitive episodes of social defeat can
decrease weigh gain, food intake, and leptin levels in intruder animals along with increased cor-
ticosterone, ACTH, and body temperature (Raab 1986; Meerlo 1996; Koolhaas1997; Ruis 1999;
Bhatnagar 2006). Increased food intake (although only during the light phase) in the presence of
decreased body weight has also been reported (Bhatnagar 2006). In mice the combination of this
stressor with a high‐fat diet regimen is able to induce an overall increase in adipose fat mass, but
not body weight gain, in the absence of any change in food intake. As will be described later, this
effect seems to be mediated by the NPY/Y2R system in the adipose tissue (Kuo 2007). In ham-
Handbook of Neurobehavioral Genetics and Phenotyping
68
sters intermittent chronic social defeat increases weight gain, food intake, and adipose depots as
well as plasma levels of leptin in the absence of any change in corticosterone, ACTH, or insulin
(Foster 2006). In this species a clear‐cut difference between dominant and subordinate liability
to weight gain, increased food intake, white adipose masses, and leptin serum levels has been
also demonstrated (Solomon 2007).
Chronic Psychosocial Stress, Sensory Contact, andChronic Defeat stress
The sensory contact (also known as chronic defeat stress) and the chronic psychosocial stress
models are very similar and based on male mouse aggressive behavior. Two unfamiliar male
mice are paired and allowed to aggressively interact for a short period of time daily; they are left
thereafter in sensory contact allowed by a perforated partition in the housing cage. A dominant
and a subordinate mouse can be identified by behavioral observations. The vast majority of the
studies so far have focused on the metabolic consequences in the subordinate mice. Accordingly,
unless otherwise stated, we will refer to the phenotype of subordinate mice only. The sensory
contact model was originally developed in C57BL/6J mice by Kudryavsteva and colleagues
(review Kudryavsteva 1991a,b, 1998, 2000, 2003, 2010) and later modified and popularized by
Nestler`s group (Berton 2006; Tsankova 2006; Krishnan 2007; Lutter 2008a,b) to induce behav-
ioral changes relevant for human major depression. In this paradigm, mice dyads are composed
of an experienced aggressive mouse (CD1) and an intruder mouse (usually C57BL/6J) allowed
to live in sensory contact and to interact on a daily basis for several days/weeks. The defeated
intruder mouse is moved to the cage of a different CD1 mouse on a daily basis. Sometimes
susceptible vs. resilient mice are identified on the basis of a social avoidance behavioral test
(Berton 2006; Krishnan 2007). Recently more interest has been shown in the metabolic conse-
quences of this model (Lutter 2008a,b; Chuang 2010a,b, 2011; Kumar 2013). A decrease in
body weight is consistently being reported during the stress experience (Chuang 2010b;
Krishnan 2007; Rodríguez‐Sureda 2007), mostly in correspondence with increased corticoster-
one and ghrelin levels (Lutter 2008a). Interestingly only one study demonstrated stress‐induced
weight gain in the same model in a selection of susceptible individuals without any effect on
food intake (Tsuneki 2013). These mice also showed glucose intolerance in the glucose toler-
ance test (GTT) but normal insulin, leptin, and homeostatic model assessment of insulin resist-
ance (HOMA‐IR).
In the chronic psychosocial stress model, stable dyads of male mice live chronically in sen-
sory exposure and interact physically on a daily basis (Bartolomucci 2001, 2004, 2005). The
model was originally developed with CD1 mice but has been optimized to be used with several
inbred and transgenic mice (e.g., Bartolomucci 2010; Dadomo 2011). As for the sensory con-
tact model, the outbred CD1 is the only reliable dominant. The model was originally character-
ized as a model of depression and immune–endocrine changes (see Bartolomucci 2005 for
review). Subordinate mice show a clear positive energy balance with increased weight and fat
mass (Bartolomucci 2004, 2009; Sanghez 2013). What appears to be triggering the cascade of
metabolic events leading to positive energy balance is increased food intake (Bartolomucci
2004, 2009, 2010; Dadomo 2011). Furthermore, subordinate mice have been shown to prefer
kilocalories from fat when offered a choice between pure macronutrients (Moles 2006) or to
prefer standard vs. high‐fat diet (Patterson 2013). Positive energy balance is also associated
with decreased energy output, i.e., low locomotor activity while energy expenditure is only
marginally increased (Bartolomucci 2004, 2009; Dadomo 2011; Sanghez 2013). Subordinate
mice show a hyperactive HPA axis and when fed a high‐fat diet show hyperglycemia, hyperin-
sulinemia, lipid dysfunction, glucose intolerance, and insulin resistance (Patterson 2013;
Sanghez 2013). Interestingly, dominant mice display an overall negative energy balance (body
weight loss and reduced fat mass) despite increased food intake which is due to increased
4 How does Stress Affect Energy Balance? 69
energy expenditure and sympathetic hyperactivity (Moles 2006; Bartolomucci 2009, 2010). It is
remarkable that dominant mice are metabolically healthy in spite of the observed sympathetic
hyperactivity (Sanghez 2013).
Stress, Recovery, andMaintenance: Insights onAdaptive andMaladaptive
EffectsofStress
Long‐term consequences of stress on metabolic function have also, although not extensively,
been investigated after the cessation of the stress protocol, i.e., in the recovery phase. In the
recovery phase previously stressed animals are usually individually housed and, as will emerge
from the discussion below, the overall effect consistently consists of a reversal of the catabolic
or anabolic effect exerted during the application of the stress procedure. Overall this suggests
that at least some of the stress‐induced effects are reversible. In at least one instance, the recov-
ery (isolation) took place maintaining some features of a social stress protocol (i.e., avoiding the
full interaction/defeat but maintaining the sensory contact between dominant and subordinate
mouse in a model of chronic psychosocial stress) with the overall effect of a persistence of the
stress‐induced metabolic effect (Moles 2006).
When subordinate rats are removed from the visible burrow system environment and
allowed to “recover” in individual housing, they immediately become hyperphagic and quickly
regain the lost weight primarily as fat, resulting in greater overall and visceral adiposity than
dominant and control rats. This effect is further enhanced in rats exposed to a second cycle of
visible burrow system stress and recovery. Consistent with increased adiposity, subordinates
have elevated plasma leptin and insulin levels (Tamashiro 2007a, 2011). Even following two
cycles of the visible burrow system, subordinate rats still present greater insulin sensitivity com-
pared to dominant and control rats, indicating increased glucose uptake and storage in visceral
adipose tissue which results in an increase of de novo lipogenesis in adipose tissue causing the
gain in fat mass (Tamashiro 2011). From a behavioral standpoint, the impact of stress on food
intake and body weight in subordinate animals is associated with different feeding strategies
during visible burrow system stress and recovery (Tamashiro 2004, 2007a; Melhorn 2010).
Most of the positive effects on energy balance attributed to the sensory contact or social
defeat stress model are indeed observed only after several weeks of recovery in individually
housed mice. Mice show a reversal of stress induced weight loss: previously subordinated mice
gain weight and fat mass due to hyperphagia due to increased meal size (Chuang 2010a,b;
Kumar 2013). At the endocrine level, leptin production remains suppressed, and ghrelin secre-
tion is increased to induce a potent feeding response that increases available energy stores
(Lutter 2008a; Chuang 2011). Previously stressed mice also show a decrease in fatty acid syn-
thase in white adipose tissue and increased hypothalamic expression of the orexigenic neuro-
peptides NPY and AgRP. This activation of NPY/AgRP neurons can then stimulate food intake
and body weight after chronic stress and promote the use of carbohydrates as fuel while spar-
ing fat. Interestingly, high‐fat diet availability does not seem to worsen the metabolic pheno-
type of mice previously subjected to chronic social defeat (Chuang 2010a,b) and they actually
develop less fat mass and associated leptin rise than control mice on a high‐fat diet, in the
presence of higher cholesterol levels (Chuang 2010a,b). When access to a high‐fat diet is lim-
ited to a few days throughout recovery (Chuang 2011), previously defeated mice exhibit hyper-
phagia and increase body weight gain compared to controls. It must be noted however that
social isolation exerts metabolic consequences per se (see discussion above) with potential con-
founding effects on the metabolic sequelae of social stress in rodents (Nonogaki 2007). For
example, it has been demonstrated that chronic social stress has CNS effects only when isola-
tion follows the social stress but not if animals are group housed (Ruis 1999; Isovich 2001).
Handbook of Neurobehavioral Genetics and Phenotyping
70
Only recently has the recovery from chronic psychosocial stress been investigated.
Interestingly, subordinate mice isolated following the end of the stress show an overall drop in
body weight while food intake remains elevated, in the presence of increased energy expendi-
ture and adiposity (Patterson 2013). Furthermore, previously stressed mice present increased
visceral fat with larger adipocytes, heavier brown adipose tissue, hyperinsulinemia, hyperlep-
tinemia, hyperglycemia, elevated basal corticosterone levels, and increase of IL‐6–all indica-
tive of increased adiposity and coexisting with increased expression of the hypothalamic
orexigenic NPY and AgRP signaling pathways (Patterson 2013). On the contrary, it has been
shown that both the positive energy balance in subordinate mice and the negative energy bal-
ance in dominant animals can persist if the stress phase is followed by partial “maintenance” of
the stress phase conditions (Moles 2006).
The recovery from unstable social settings stress has also been investigated. Interestingly,
adult mice that experienced social instability at adolescence showed differential fat distribution
compared to controls a year after the cessation of the stress (Schmidt 2009). Nevertheless this
phenotype cannot yet be related to a specific set of biomarkers and it must be noted that isola-
tion stress might have played a role as the mice were single‐housed for the whole length of the
recovery phase.
The recovery from non‐social stress models has also been investigated. At least one study
addressed the recovery from chronic mild pain, demonstrating persistent negative energy bal-
ance after the cessation of the stress as the stress‐induced loss of body weight is not recovered
in spite of normalized levels of food intake (Levine and Morley 1981). The alterations induced
by chronic mild stress can normalize following cessation of the stress regimen (Flak 2011).
Interestingly, the recovery occurs with a delay compared to the timing of weight loss/recovery
observed in animals where the same weight loss seen in restrained animals is induced through
food restriction only. This would indicate that stress attenuates weight gain independently
from effects on metabolic parameters. In the recovery from restraint stress a compensatory
hyperphagic phase may occur (Depke 2008). Depending on the severity of the stress‐induced
body weight loss, restrained rats might fail to return to the body weight of control animals
(Kennett 1986; Shimizu 1989; Krahn 1990) or they might show a complete normalization
(Babenko 2012). There is now evidence in support of different timing required by different
metabolic parameters to normalize in recovery. For example, carbohydrate metabolism might
be still altered several weeks after the cessation of stress, when hyperglycemia through increased
activity of hepatic enzymes is still observed (Nirupama 2012).
Molecular Mechanisms of Stress-Induced Negative and Positive
Energy Balance
The “neuro‐symphony of stress” is emerging (Ulrich‐Lai and Herman 2009; Joëls and Baram2009)
and very elegant pharmacogenomics studies are revealing the neurocircuitry of eating and energy
expenditure (e.g., Balthasar 2005; Kong 2012). However, very limited work has been conducted
on the involvement of the same neurocircuitry on positive and negative energy balance. The
mechanistic studies are mostly focused on hypothalamic neuropeptides, adipocytes, and gut‐
derived peptides as well as classical neurotransmitters.
Overall, our understanding of the molecular mechanisms of stress‐induced negative and
positive energy balance is still in its infancy (see Razzoli 2016 for an updated review). This
could be due at least in part to the confusion generated by the different, sometimes opposite,
phenotypes induced by similar models as reviewed above. Furthermore, because the HPA axis
is activated by acute stressors and is up‐regulated by chronic stress, it is generally assumed that
4 How does Stress Affect Energy Balance? 71
glucocorticoid‐mediated metabolic effects should be observed in mice exposed to stress mod-
els. This assumption is mostly incorrect because it does not take into account the parallel acti-
vation of many other stress‐related pathways including the SNS and the SAM axis which affect
metabolism in a direction that is usually opposite to glucocorticoids. For example, the “comfort
food” hypothesis, usually discussed as the mechanism linking stress and HPA axis activation to
obesity, was originally tested in rats exposed to restraint stress where the restraint‐induced
negative energy balance was only partially reversed by preference for comfort hypercaloric
food (Pecoraro 2004). On the contrary, in the absence of stress and in the presence of insulin,
glucocorticoids determine a net positive energy balance and visceral fat accumulation (Rebuffé‐
Scrive 1992; la Fleur 2004; Pecoraro 2004). Accordingly, the activation of the HPA axis might
be necessary but not sufficient to explain the development of stress‐induced positive energy
balance (Sapolsky 2000).
Serotonin (5‐hydroxytryptamine, 5HT)
5HT is a neurotransmitter found in central and peripheral tissues (Murphy and Lesch 2008). In
the CNS 5HT is synthesized by the serotonergic neurons that extend their projections from the
raphe nuclei to several brain regions where they regulate food intake, energy expenditure, and
energy homeostasis. Importantly, mice and humans with mutations in the 5‐HT2CR are char-
acterized by hyperphagia and locomotor hyperactivity (Nonogaki 1998, 2003; Vickers 1999).
5HT acting on 5HT2CR would inhibit ghrelin activity by directly activating POMC/CART neu-
rons and inhibiting ghrelin/NPY signaling, causing a decrease in food intake and shifting the
phenotype towards a negative energy balance (Fujitsuka 2009). Central treatment with seroto-
nin reuptake inhibitors, which prolong the availability of serotonin in the synaptic cleft, high-
lighted 5HT’s role in energy metabolism by increasing food intake, body weight, and body
temperature (Saller and Stricker 1976; Waldbillig 1981; Li 1999; Holmes 2002). SLC6A4, the
gene encoding the 5HT transporter protein (5HTT), presents a short and a long allelic variant
that is associated to diminished and increased transcriptional activity of the transporter,
respectively. Similarly to the pharmacological inhibition of the serotonin transporter, 5HTT
knockout mice display an overall positive energy balance along with lower locomotor activity
and basal plasma corticosterone levels; furthermore they present a dramatic stress hypersensi-
tivity to acute and chronic stimulation (Tjurmina 2002; Holmes 2003; Murphy and Lesch 2008).
5HTT heterozygous mice have an increased behavioral vulnerability but normal metabolic vul-
nerability to chronic psychosocial stress which could be due to a lower serotonin turnover in
different brain nuclei (Bartolomucci 2010; Boyarskikh 2013).
Orexin
Orexins, also called hypocretin (two existing forms, orexin‐A and –B, which will be referred to
as orexins in this review), are neuropeptides synthesized in the perifornical, lateral, and poste-
rior hypothalamic area (Peyron 1998; Nambu 1999). Signaling through OX1R, a G‐protein
coupled receptor, orexin regulates sleep/wakefulness, appetite/metabolism, energy expendi-
ture, stress response, reward/addiction, and analgesia (Berridge 2010; Teske 2010; Kukkonen
2013). In rats, central orexin administration increases food intake, while the opposite effect
occurs with the administration of anti‐orexin antibodies (Sakurai 1998; Yamada 2000).
Moreover OX1R antagonist decreased food intake, body weight, fat mass, and fasting glucose
while it increased insulin sensitivity and energy expenditure in ob/ob mice (i.e., mice lacking
the leptin peptide, see below). Cold exposure and restraint stress have been reported to activate
orexin neurons in rats (Berridge 1999; Ida 2000; Zhu 2002). Orexin‐expressing neurons are
thought to be involved in the stress response through direct effects on the hypothalamic
Handbook of Neurobehavioral Genetics and Phenotyping
72
CHR/AVP neurons that are central in the stress responses, as well as indirect effects through
the brainstem (Nishino and Sakurai 2005). After chronic sensory contact stress associated with
caloric restriction, only wild type (wt) stressed mice display increased social interaction, while
orexin knockout (−/−) mice are unaffected, suggesting that orexin plays a role in the stress and
caloric restriction induced behavioral changes (Lutter 2008b). Moreover, wt stressed mice
showed increased histone demethylation of the orexin promoter leading to down‐regulation of
orexin mRNA expression and orexin neurons in the lateral hypothalamic area, thus suggesting
that chronic stress impairs orexin signaling, decreasing the ability to cope with chronic stress
(Lutter 2008b). Interestingly, stress susceptible (determined by social avoidance) orexin −/−
mice show a reversal of chronic sensory contact stress‐induced weight gain without any effect
on food intake (Tsuneki 2013). Remarkably this is the only study showing a positive energy
balance for this model of stress (see Tables 4.1 and 4.2). Furthermore, orexin −/− stressed mice
but not wt mice exhibit increased HOMA‐IR, hepatic glucose production, and hyperinsuline-
mia. Surprisingly, despite having higher insulin resistance, stressed orexin −/− mice showed an
almost normalized stress‐induced glucose intolerance as observed in wt mice. Thus central
actions of orexins appear to be required to prevent the rapid development of hepatic insulin
resistance under chronic stress conditions (Tsuneki 2013). Indeed hypothalamic orexin can
increase plasma corticosterone levels, which in turn modulate hepatic glucose production via
the sympathetic nervous system, thus suggesting that orexins are essential neurotransmitters
in maintaining altered glucose and insulin metabolism responses to chronic stress (Yi 2009).
Neuropeptide Y (NPY)
NPY is the most abundant neuropeptide in the brain. It is the most potent orexigenic factor and
is involved in regulation of energy metabolism with actions in the central and peripheral nerv-
ous system (Wettstein 1995; Zukowska‐Grojec 1995). Its biological effects are mediated by at
least six G‐protein coupled receptors, Y1 to Y6, which are widely and differently distributed in
the CNS and the periphery (Parker and Herzog 1999). In the CNS the main function of NPY is
to promote hyperphagia and anxiety by binding to Y1 and Y5 receptors (Lecklin 2002; Bertocchi
2011). NPY also influences energy balance by decreasing energy expenditure as thermogenesis
in brown adipose tissue and increasing LPL activity in white adipose tissue (Kotz 2000).
However, NPY also co‐localizes with NE‐secreting sympathetic neurons in several peripheral
tissues. Under specific stimuli both NPY and NE are released from the sympathetic nerve ter-
minals (Lundberg 1983; Callanan 2007). In adipose tissue NPY is known to have anti‐lipolytic
properties (Kuo 2007), reducing the rate of lipolysis and enhancing fat deposition (Valet 1990).
Mice exposed to cold stress or intermittent social defeat stress models and fed a high‐fat diet
showed increased fat mass as well as glucocorticoids, NPY, NPY2R and dipeptidyl peptidase IV
(DPPIV) mRNA in perigonadal white adipose tissue (Kuo 2007). A Y2R agonist determined an
obese phenotype and positive energy balance, both of which can be reversed by a Y2R antago-
nist (Kuo 2007). Accordingly germline Y2R −/− mice exhibit reduced adiposity when exposed
to stress (Kuo 2007). It has been hypothesized that cold stress and to a certain extent repeated
social defeat associated to a high‐fat diet could activate the NPY/Y2R pathway that promotes
adipogenesis by blunting the NE/βAR signaling in white adipose tissue (Kuo 2007, 2008).
Ghrelin andGrowth Hormone Secretagogue Receptor (GHSR)
Ghrelin is a hormone secreted by the gastrointestinal tract that rises before meals and stimu-
lates hunger and meal initiation (Kojima 1999; Cummings 2005). Ghrelin circulates in two
forms, acyl‐ghrelin and des‐n‐octanoyl ghrelin (des‐acyl ghrelin). While acyl‐ghrelin activates
the growth‐hormone secretagogue receptor, des‐acyl ghrelin does not. GHSR are distributed
4 How does Stress Affect Energy Balance? 73
mainly in the catecholaminergic and dopaminergic neurons of the ventral tegmental area
(VTA) as well as in some peripheral tissue (Gnanapavan 2002; Abizaid 2006). Centrally, ghrelin
promotes orexigenic effects by stimulating the orexigenic NPY/AgRP neurons in the hypotha-
lamic feeding centers; peripherally it facilitates the accumulation of adipose tissue by inhibiting
fat utilization in adipose tissue, overall favoring an obesogenic phenotype and positive energy
balance. Ghrelin also promotes fat mass accumulation and suppresses sympathetic nerve activ-
ity (in brown adipose tissue) decreasing energy expenditure (Tschöp 2000; Davies 2009; Otagiri
2009). However, the functional significance of GHSR or ghrelin genetic ablation is still contro-
versial (Sun 2003; Wortley 2004). Generally, knockout mice for either ghrelin or GHSR show
only a mild metabolic phenotype that is mostly composed of decreased body weight and adi-
posity in the absence of altered feeding behavior or activity (Sun 2003, 2004; Wortley 2004;
Longo 2008). Negative energy balance develops in GHSR knockout mice only following several
weeks of a high‐fat diet (Zigman 2005). GHSR −/− mice are hypophagic and have increased
energy expenditure but normal locomotor activity; overall they are resistant to diet‐induced
obesity compared to wt mice. Ghrelin plasma levels are elevated after several types of stress in
human and rodent models (e.g., Kristensson 2006; Mundinger 2006; Rouach 2007; Ochi 2008).
In contrast plasma ghrelin level is lower in obesity and diabetes (e.g., Tschöp 2001; McLaughlin
2004). Chronic psychosocial stress or sensory contact stress models increase plasma concen-
tration of acyl‐ghrelin (Lutter 2008a; Chuang 2011; Patterson 2013). Because of the discrepan-
cies in the metabolic effects of the two stress models it is difficult to interpret the present
findings. Furthermore Patterson and coworkers (2013) clearly showed that subordinate mice
exposed to chronic psychosocial stress show weight gain and hyperphagia, both of which are
reversed by genetic deletion of the ghrelin receptor (GHSR −/− mice) and treatment with ghre-
lin receptor antagonist ([D‐Lys3]‐GHRP‐6). Conversely, Lutter and coworkers (2008b) showed
that genetic deletion of the GHSR prevents chronic social defeat stress‐induced hyperphagia
without any effect on body weight. It must be noted, however, that in Chuang etal.s study
(2011) defeated mice did not show the weight loss demonstrated by the same group in other
studies (Table 4.2). Accordingly it is difficult to interpret the present findings. Nevertheless the
role of ghrelin and GHSR in mediating the rewarding properties of stress on a high‐fat diet in
a conditional place preference test has been well documented (Chuang 2011).
Glucagon like Peptide 1 (GLP1)
GLP1 is derived from the transcription product of the proglucagon gene. The major source of
GLP1 in the body is the intestinal L cells (Holst 2007). GLP1 primarily influences the absorp-
tion process and is a potent stimulator of insulin secretion with significant effects on the regu-
lation of glucose metabolism (Vella and Rizza 2004). However GLP1 is also centrally expressed
in the NTS and ventrolateral medulla that directly innervate the hypothalamic PVN (see
Ghosal 2013 for review). GLP1 neurons play a crucial role in regulating HPA axis functions
during basal and stress conditions (Kinzig 2003). For example, in rats under chronic mixed
stress, chronic central administration of GLP1 induces HPA hyperactivity and decreases
basal glucose levels and body weight gain. Since food intake is unchanged, GLP1 might be
influencingbody weight by acting on energy expenditure, although the exact mechanism is still
unclear(Tauchi 2008).
Leptin
Encoded by the ob gene (Zhang 1994), leptin is primarily secreted by white adipocytes in propor-
tion to adipose mass. Leptin acts through Ob‐Rs receptors that are widely expressed both cen-
trally and peripherally. Mutations in the ob gene or in Ob‐Rs receptors result in excessive obesity,
Handbook of Neurobehavioral Genetics and Phenotyping
74
hyperinsulinemia, and hypercorticosteronemia indicating a crucial role for leptin in controlling
energy homeostasis (Schwartz 2000; Cowley 2001). Leptin resistance develops in obesity. Mice
fed a high‐fat diet and exposed to the sensory contact stress model develop leptin resistance
which seems to be associated with lower hypothalamic pSTAT3 signaling (Chuang2010b).
Amylin
Amylin is co‐secreted with insulin from the beta pancreatic cells and acts as an adiposity signal
(Wielinga 2010). In positive energy balance states, such the one induced during recovery from
the visible burrow system, chronic amylin treatment reduces food intake and body weight gain
by limiting deposition of visceral adipose tissue (Smeltzer 2012). Although the exact molecular
mechanisms behind amylin’s action are still unclear, it seems to act primarily on the NPY/AgRP
hypothalamic neurons, inhibiting NPY‐induced hyperphagia by reducing meal size, duration,
and frequency (Morris and Nguyen 2001; Melhorn 2010).
Norepinephrine andβ3‐Adrenergic Receptor
Catecholamines increase lipolysis in adipocytes and thermogenesis in brown adipose tissue
largely via activation of the βARs (Nicholls and Locke 1984; Goldman 1985; Klaus 1991;
Landsberg and Young 1992). In the sensory contact model mice lose weight during the defeat
phase and regain weight, due to hyperphagia, in the recovery phase while fat mass and leptin
remain lower than control levels. The pharmacological blockade of β3AR in this context abol-
ishes the stress‐induced hyperphagia but paradoxically normalizes stress‐induced decrease in
fat mass and leptin level (Chuang 2010b).
Conclusion
The vast majority of physical–psychological non‐social stress models as well as models of chronic
mild stress (social or non‐social) induce a negative energy balance that results in body weight
and/or fat mass loss. High‐calorie “comfort food” ingestion may limit, but not reverse, the nega-
tive energy balance induced by non‐social stressors. The only notable exception is daily short
exposure to ice‐cold water that increased fat mass in the presence of a high‐fat diet, which might
be linked to the proposed functional role of NPY as a hibernation hormone (Kuo 2007). The
metabolic effects of chronic social stress models, however, are more heterogeneous, although
when administered in the presence of a high‐fat diet a positive energy balance generally is the
outcome. Major discrepancies exist between models that appear very similar such as the sensory
contact (or chronic social defeat) model and the chronic psychosocial stress model. Overall it is
remarkable that the two models induce very similar neuroendocrine and behavioral effects but
highly divergent metabolic consequences (negative for the first and positive for the latter) at least
during the sensory contact social defeat phase. We propose that the factor responsible for this
striking difference is the stability (chronic psychosocial stress) vs. the instability (sensory contact)
of the housing environment for the subordinate animal, although this hypothesis is yet to be
tested (see Razzoli 2016 for an updated review). On the contrary, removing the mice from the
stress experience by individually housing them generally leads to a reversal of stress‐induced
effects. Finally, although poorly investigated, it is clear that social status plays a major role in
energy homeostasis in conditions of chronic stress (see Sanghez 2013 for further discussion).
The mechanistic understanding of how stress affects energy balance is still at an early stage
where hypotheses have mostly been tested with one model of stress and not generalized to
other models. On the one hand, serotonin (via 5H2C receptors and 5HTT), orexin, amylin, and
4 How does Stress Affect Energy Balance? 75
ghrelin seem to play a major central role, while peripherally NPY/Y2R receptors in the sympa-
thetic nervous system/adipocytes synapse in the adipose fat pads. Remarkably, the role of
HPA‐axis secreted hormones and catecholamines, which are crucial to both stress physiology
and energy balance, is not been unambiguously determined in the context of stress‐induced
energy balance disorders.
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Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.
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Obesity and metabolic diseases are linked to chronic stress and low socioeconomic status. The mechanistic link between stress and obesity has not been clarified, partly due to the inherent complexity exemplified by the bidirectional effect of stress on eating and body weight. Recent studies focusing on adaptive thermogenesis and brown adipose tissue (BAT) function support a dichotomous relation to explain the impact of stress on obesity: stress promotes obesity in the presence of hyperphagia and unchanged BAT function; stress results in weight loss and/or obesity resistance in the presence of hypophagia, or when hyperphagia is associated with BAT recruitment and enhanced thermogenesis. Mechanistically dissecting the bidirectional effects of stress on metabolic outcomes might open new avenues for innovative pharmacotherapies for the treatment of obesity-associated diseases.
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Stress in socially subordinate male rats, associated with aggressive attacks by dominant males, was studied in a group-housing context called the visible burrow system (VBS). It has been established that subordinate males have reduced serum testosterone (T) and higher corticosterone (CORT) relative to dominant and singly housed control males. The relationship of the decreased circulating T levels in subordinate males to changes in serum LH concentrations has not been evaluated previously. Since decreases in LH during stress may cause reductions in Leydig cell steroidogenic activity, the present study defined the temporal profiles of serum LH, T, and CORT in dominant and subordinate males on Days 4, 7, and 14 of a 14-day housing period in the VBS. The same parameters were followed in serum samples from single-housed control males. Leydig cells express glucocorticoid receptors and may also be targeted for direct inhibition of steroidogenesis by glucocorticoid. We hypothesize that Leydig cells are protected from inhibition by CORT at basal concentrations through oxidative inactivation of glucocorticoid by 11β-hydroxysteroid dehydrogenase (11βHSD). However, Leydig cell steroidogenesis is inhibited when 11βHSD metabolizing capacity is exceeded. Therefore, 11βHSD enzyme activity levels were measured in Leydig cells of VBS-housed males at the same time points. Significant increases in LH and T relative to control were observed in the dominant animals on Day 4, which were associated with the overt establishment of behavioral dominance as evidenced by victorious agonistic encounters. Serum LH and T were lower in subordinate males on Day 7, but T alone was lower on Day 14, suggesting that lowered LH secretion in subordinates may gradually be reversed by declines in androgen-negative feedback. Serum CORT levels were higher in subordinate males compared to control at all three time points. In contrast, oxidative 11βHSD activity in Leydig cells of dominant males was higher relative to control and unchanged in subordinates. These results suggest the following: 1) failure of Leydig cells of subordinate males to compensate for increased glucocorticoid action during stress, by increasing 11βHSD oxidative activity, potentiates stress-mediated reductions in T secretion; and 2) an inhibition of the reproductive axis in subordinate males at the level of the pituitary.