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The importance of estradiol
for body weight regulation
in women
Pilar Vigil
1
, Jaime Mele
´ndez
1
, Grace Petkovic
2
and Juan Pablo Del Rı
´o
3,4
*
1
Reproductive Health Research Institute (RHRI), Santiago, Chile,
2
Arrowe Park Hospital, Department
of Paediatrics, Wirral CH49 5PE, Merseyside, United Kingdom,
3
Unidad de Psiquiatrı
´a Infantil y del
Adolescente, Clı
´nica Psiquia
´trica Universitaria, Universidad de Chile, Santiago, Chile,
4
Millennium
Nucleus to Improve the Mental Health of Adolescents and Youths, Millennium Science Initiative,
Santiago, Chile
Obesity in women of reproductive age has a number of adverse metabolic
effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular
disease. It is associated with increased menstrual irregularity, ovulatory
dysfunction, development of insulin resistance and infertility. In women,
estradiol is not only critical for reproductive function, but they also control
food intake and energy expenditure. Food intake is known to change during the
menstrual cycle in humans. This change in food intake is largely mediated by
estradiol, which acts directly upon anorexigenic and orexigenic neurons,
largely in the hypothalamus. Estradiol also acts indirectly with peripheral
mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts
on receptors at the hypothalamus. This review describes the physiological and
pathophysiological mechanisms governing the actions of estradiol during the
menstrual cycle on food intake and energy expenditure and how estradiol acts
with other weight-controlling molecules such as GLP-1. GLP-1 analogs have
proven to be effective both to manage obesity and T2D in women. This review
also highlights the relationship between steroid hormones and women's
mental health. It explains how a decline or imbalance in estradiol levels
affects insulin sensitivity in the brain. This can cause cerebral insulin
resistance, which contributes to the development of conditions such as
Parkinson’s or Alzheimer’s disease. The proper use of both estradiol and
GLP-1 analogs can help to manage obesity and preserve an optimal
mental health in women by reducing the mechanisms that trigger
neurodegenerative disorders.
KEYWORDS
GLP-1, estrogens, body weight, menstrual cycle, mental health
Frontiers in Endocrinology frontiersin.org01
OPEN ACCESS
EDITED BY
Hubert Vaudry,
Universite
´de Rouen,
France
REVIEWED BY
Fernando Lizcano,
Universidad de La Sabana, Colombia
Hiroto Kobayashi,
Yamagata University, Japan
*CORRESPONDENCE
Juan Pablo Del Río
delrio.juanpablo@gmail.com
SPECIALTY SECTION
This article was submitted to
Neuroendocrine Science,
a section of the journal
Frontiers in Endocrinology
RECEIVED 23 May 2022
ACCEPTED 18 October 2022
PUBLISHED 07 November 2022
CITATION
Vigil P, Mele
´ndez J, Petkovic G and
Del Rı
´o JP (2022) The importance of
estradiol for body weight regulation
in women.
Front. Endocrinol. 13:951186.
doi: 10.3389/fendo.2022.951186
COPYRIGHT
© 2022 Vigil, Mele
´ndez, Petkovic and
Del Rı
´o. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s)
are credited and that the original
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accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms.
TYPE Review
PUBLISHED 07 November 2022
DOI 10.3389/fendo.2022.951186
Introduction
Obesity, defined as a body mass index (BMI) ≥30, affects
around 42% of adults in the United States (1). During the period
2017-2018, women had a higher prevalence of severe obesity
(BMI ≥40 kg/m
2
) than men (11.5% vs. 6.9%, respectively) (1),
though overall obesity prevalence rates were similar (42.1% and
43.0%, respectively).
Obesity is associated with a number of disorders that affect the
reproductive system. Such disorders include: ovulatory dysfunction,
such as found in polycystic ovary syndrome (PCOS); disorders of
pregnancy, (e.g., preeclampsia, gestational diabetes, and recurrent
pregnancy loss), endometriosis; and cancers (2,3). There is growing
concern about how the increasing obesity rate in adolescent women
will impact their long-term health. The prevalence of obesity among
adolescent girls (12–19 years) in 2015/2016 was 20.9% (4)and3–
11% of these obese adolescent girls had PCOS (5,6). This may be
explained by the fact that obesity and related comorbidities, such as
insulin resistance, alter the functioning of the hypothalamic–
pituitary–ovarian axis, decreasing ovarian responsiveness to
gonadotropin stimulation (3,7). Insulin also stimulates follicular
growth through its action at the theca cells (8). This causes
disorganized follicular growth and increases ovarian production
and secretion of testosterone (9). Ultimately, this can, in turn, affect
ovulation. Amongst PCOS patients, those who are obese are most at
risk of insulin resistance (10). By contrast, only half (50%) of normal
weight PCOS patients are insulin resistant (9).
The reproductive system modulates body weight regulation.
Food intake is known to change during the menstrual and/or
estrous cycle, with women significantly reducing their food
intake in the peri-ovulatory period (11–13). Therefore, in
principle, ovulatory dysfunction may increase the risk of
obesity, as women will lack this usual period of “reduced
appetite”. This link between reproductive function and body
weight control is largely mediated by the female sex steroid
hormones, particularly estradiol and progesterone. In general,
estradiol regulates homeostatic nutrition in women by
decreasing food intake and increasing energy expenditure (13)
(Figure 1). Female reductions in food intake during the peri-
ovulatory period are a consequence of the anorectic action of
estradiol. Estradiol acts at the level of the cortex, hypothalamus
and brainstem (14). The anorectic and thermogenic effects of
estradiol can be direct, through genomic and non-genomic
mechanisms, or indirect, through activation of peripheral
mediators such as cholecystokinin (CCK), insulin, leptin and
GLP-1.
A reduction in estradiol levels, as found in the menopause,
would therefore be expected to result in increased food intake
(with the estradiol activity lost). Thus, a loss of estradiol post-
menopause, may contribute to the development of obesity, and
systemic and cerebral insulin resistance (15). Insulin resistance
and T2D, both of which are associated with obesity and
ovulatory dysfunction, cause abnormalities in the proper
functioning of the central nervous system (CNS). Indeed, both
are linked to neurodegenerative disorders (15,16). Estradiol and
GLP-1 (and its analogs) have been proposed as novel therapeutic
approaches to restore not only body weight in women but also to
prevent the development of neurodegenerative disorders
(17,18).
This review describes the physiological and pathophysiological
mechanisms that govern the actions of estradiol on food intake and
energy expenditure duringthemenstrualcycle(13). We highlight
how GLP-1 and estrogen are thought to have synergistic effects and
summarize recent work on the use of GLP-1 conjugates as agents to
manage obesity, T2D and central insulin resistance. Finally, we
consider potential future uses of estradiol and GLP-1 conjugates in
protecting against cerebral insulin resistance, and resultant
neurodegenerative disorders.
Menstrual cycle and appetite
control: Implications for
weight regulation
The CNS, particularly the hypothalamus, plays a key role in
homeostatic feeding. Brain nuclei such as the nucleus of the
solitary tract (NST), the arcuate (ARC), the paraventricular
region of the hypothalamus (PVH), control meal size of and
modulate feelings of satiety. Additional brain regions are also
involved in feeding. Such regions include: the primary and
secondary taste regions (insula and orbitofrontal cortex); as
well as the hippocampus; and cognitive control regions
(dorsolateral prefrontal cortex, inferior frontal cortex and
cingulate cortex) (19,20). Eating behavior depends on the
simultaneous operation of these homeostatic pathways
together with a more flexible non-homeostatic pathway. The
non-homeostatic pathway differs between individuals because of
variations in hormonal status, epigenetic markers and personal
experiences. Evidence from human and animal studies indicates
that food intake fluctuates during the menstrual cycle, because
gonadal steroid hormones (estradiol and progesterone) are key
regulators of energy uptake.
There is strong evidence for a link between the menstrual
and/or estrous cycle and appetite. For example, in laboratory
studies, ovariectomized female rats increase their food intake.
Their food intake can be normalized by the administration of
physiological doses of -estradiol but not progesterone (11,13,21,
22). Other behavioral studies in rats have also demonstrated that
estradiol controls meal size (23). In clinical studies, food intake is
lower in the periovulatory phase and greater in the early
follicular and luteal phases (11,24,25). The periovulatory
decrease in food intake coincides with a surge in circulating
estradiol levels and is the result of decreased meal size rather
than decreased meal frequency (26,27). The types of foods eaten
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also change with the menstrual cycle. Food cravings and binge
eating of specific food items are reported more frequently by
women in the luteal phase (28–30). Most (29–38) though not all
(39–41) studies, have shown increased caloric intake in the luteal
phase. The specific macronutrient composition of the increased
calories consumed in the luteal phase varies, but most often
results from either increased fat (32,35,38) or carbohydrate
intake (35,36,38). Intake of sweet foods also decreases in the
peri-ovulatory period (29,42) and protein intake increases in the
luteal phase (43). Orosensory stimuli affect organism’s selection
and preference for particular foods. Estradiol levels affect how
women psychologically perceive food (13,44,45). Across the
menstrual cycle, neuronal responses to images of food change
(46–49). When a subject is presented with high energy-food
pictures in the periovulatory (as compared with the luteal
phase), the brain areas linked to food intake show increased
responsiveness (44). Dopaminergic reward activity to high
energy foods is enhanced in the periovulatory phase (50,51).
Although the evidence is still controversial, the odor detection
threshold may vary across the menstrual cycle. The threshold
appears lower during the ovulatory and luteal phase (when
estradiol levels are high) and higher during menstruation and
early follicular phase (when estradiol levels are low) (44,47,52).
Interestingly, it seems that the usual cyclical change in food
intake is absent in anovulatory cycles (33,43). This is explained
by the absence of the estradiol´s rise and fall, impacting both
appetite and ovulation. Anovulatory cycles can be associated
with either low or, by contrast, constantly elevated estradiol
FIGURE 1
Potential interaction between meal-related gastrointestinal signals and estradiol on control of the body weight in women. Meal-related
gastrointestinal signals (CCK, GLP-1, others) act through a paracrine-neuronal pathway (shown in purple and red). These meal-related
gastrointestinal signals act paracrinally upon vagal afferent neurons (VAN). The VANs activate secondary neurons located in the NTS, in the
brainstem. The NTS integrates a variety of peripheral signals, and in turn activates tertiary neurons located in different nuclei in the
hypothalamus. These hypothalamic nuclei control feeding behavior. Circulating estradiol (shown in green) modulates the responsiveness to
these gastrointestinal satiety signals by acting on all levels of this paracrine-neuronal pathway: The VAN, NTS and the hypothalamic nuclei.
Gastrointestinal satiety signals also act directly upon the hypothalamic nuclei through a hormonal pathway (shown in purple). Additionally,
estradiol (green) has a direct anorexigenic effect at the level of the hypothalamic nuclei (PVH, LH and ARC), thereby reducing food intake.
Metabolic signals such as insulin and leptin also influence centers in the hypothalamus to regulate body weight. Brown adipose tissue (BAT)
thermogenesis contributes to regulation of body weight by increasing energy expenditure. Estradiol acts all three points of the VMH-SNS-BAT
pathway to increase thermogenesis. Within the VMH hypothalamic nucleus, estradiol acts by inhibiting AMPK. Thus, estradiol increases energy
expenditure by increasing BAT thermogenesis, and WAT browning. This, in combination with estradiol’s effects to decrease food intake, can
result in weight loss. NST, nucleus of the solitary tract; DMH, dorsomedial hypothalamus; LH, lateral hypothalamus; PVH, paraventricular
hypothalamus; ARC, arcuate nucleus; VMH, ventromedial hypothalamus; BAT, brown adipose tissue; WAT, white adipose tissue.
Vigil et al. 10.3389/fendo.2022.951186
Frontiers in Endocrinology frontiersin.org03
levels (53). Both estradiol states could be linked to increased
appetite. Evidently, a low estradiol level may be insufficient to
trigger the usual anorectic effects. However, it may also be that at
constant, high levels of estradiol (as in anovulatory cycles, or in
hormonal preparations), its anorexic effects are blunted.
Menstrual cycle and eating disorders
In addition to influencing food intake in healthy states,
estradiol and progesterone have also been implicated in the
etiology and expression of eating disorders (54–56). Eating
disorders are one of the most sex differentiated forms of
psychopathology, with the female-to-male ratio ranging from
4:1 to 10:1 (57). Binge eating and emotional eating are
significantly higher during the mid-luteal and pre-menstrual
phases of women’s menstrual cycle as compared to the follicular/
ovulatory phases (54,55,58,59). Progesterone levels are
positively associated with increased binge eating across the
menstrual cycle (54,55). Whilst physiological levels of
estradiol are inversely associated with binge eating, it appears
that abnormally high levels of estradiol are actually positively
associated with binge eating and emotional eating (13).
Importantly, in all previous studies, hormonal effects on binge
eating and emotional eating were independent of covariates that
could also change across the menstrual cycle, such as negative
affect and body mass index (BMI) (54,55,59,60). Laboratory
studies suggest estradiol may act on serotonergic neurons to
inhibit binge eating (61) and this effect is partially mediated by
insulin. Thus, increased insulin resistance may decrease the
serotonergic neurons responsiveness to estradiol. This in turn,
may increase the risk of binge eating. Even in healthy women,
increased insulin resistance has been reported during the luteal
phase of the menstrual cycle in healthy women (62). This could
partially explain the differences in eating behavior observed
across the menstrual cycle. Evidence suggests that women with
an eating disorder may display differential insulin sensitivity to
the changes in ovarian hormone levels (60,62,63).
It is interesting to speculate as to whether progesterone-only
contraceptives could indirectly alter insulin sensitivity (64,65).
Many women receive progesterone only medications. Such
medications disrupt the normal ovulatory process. Estradiol
levels are therefore decreased (66). This reduction in estradiol
and its insulin sensitizing effects could potentially decrease food
intake and body weight in some women (67).
Gonadotropins and adiposity
Although, gonadotropin hormone analogs have been used
clinically for decades in assisted reproductive therapies and in
the treatment of various infertility disorders (68), novel
applications of gonadotropins targeting extra-gonadal tissues
(69), especially adipose tissue and liver are emerging (70–73).
Recent evidence suggests a possible role for FSH in regulating
lipid metabolism and fat accumulation.
Postmenopausal women have low estradiol, elevated FSH,
concomitant bone loss, and increased body fat). The rise of FSH
at menopause in response to ovarian failure has been associated
with menopausal adiposity (70) and hepatic steatosis (72)in
women. Using mouse models, high circulating FSH has been
confirmed as a major contributor to gonadectomy-induced
obesity (70–72). hese findings suggested that FSH, as well as
low estradiol, are potential targets for controlling fat
accumulation and treating obesity.
In an ovariectomized mouse model, an antibody (for
humans and mice) to FSHb(was initially found to inhibit
bone resorption and stimulate bone synthesis (61). Later, the
same antibody was found to increase BAT thermogenesis and
prevent (71) ovariectomy-induced weight gain and fat
accumulation in mice (74). Mechanistically, FSH vaccination
treatment inhibited lipid biosynthesis by inactivating PPARg
adipogenic signaling pathway and simultaneously enhancing
adipocyte thermogenesis via upregulating UCP1 (uncoupling
protein 1) expression in both visceral and subcutaneous adipose
tissues (74).
Although evidence that FSH is a key factor in fat
accumulation is robust, this is so far applicable only to some
rodent models. Thus far, there are contradictory findings in both
human and other rodent studies.
Estradiol pathways in the regulation
of body weight
Estradiol mechanisms of action
As mentioned earlier, the hypothalamus integrates most of
the neural and humoral afferent signals coordinating energy
intake and expenditure (19). Among hypothalamic nuclei, the
effects of the ARC on appetite are well-studied. The ARC
contains two main types of neuronal systems: appetite-
suppressing POMC neurons (75,76); and, appetite-stimulating
NPY/AgRP neurons (75,77). Both these neuron systems express
estrogen receptors: ERais predominantly expressed in the
POMC (proopiomelanocortin) neurons, while both ERaand
ERbare present in neuropeptide Y (NPY) and agouti-related
protein peptide (AgRP) neurons (78,79).
POMC is a precursor polypeptide, which after being
released, is cleaved into smaller active peptides. One such
peptide (a-MSH) is particularly important for appetite control.
a-MSH is most known for its role in melanin production in skin
through the activation of MC1R. However, it has an
anorexigenic effect when it activates other receptors (MC3R
and MC4R) located in the ARC and lateral hypothalamus (LH)
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(75). Indeed, mice that are deficient for MC4R or POMC are
characteristically obese due to hyperphagia (80,81). Estradiol
has an anorexigenic effect by increasing POMC neuronal
activity. Estradiol’s action on these neurons is both direct and
indirect. Estradiol indirectly increases POMC activity through its
effects on NPY/AgRP neurons (82,83). Estradiol inhibits NPY/
AgRP neurons primarily through glutamate and b-endorphin
release (84). NPY and AgRP antagonize the action of a-MSH on
MC3R and MC4R, thus having an orexigenic effect (85). Mice
that overexpress AgRP are hyperphagic and obese. MC4R is also
known to be important for appetite control in humans. MC4R
mutations are the most frequent cause of monogenic obesity in
humans (75).
Estradiol also decreases appetite directly by increasing
anorexigenic gene expression in POMC neurons and
decreasing the expression of orexigenic genes in NPY/AgRP
neurons (84,86). Interestingly, as female rats get older, these
genes become less responsive to estradiol (87). Estradiol also has
non-genomic effects. These effects are mediated by: Gq-mER
(Gq-coupled membrane ER); GPER (G-protein-coupled
estrogen receptor); and by ERaand ERbpresent in the plasma
membrane (88–91). Gq-mER is present in the hypothalamus
and its expression is restricted to NPY/AgRP neurons where it
decreases neuronal activity (82,83,92). GPER is expressed in a
number of other hypothalamic nuclei, such as the PVH, the
supraoptic nucleus and the medial preoptic area (mPOA) (93).
GPER deficiency causes increased adiposity, insulin resistance,
and metabolic dysfunction in mice (90).
Estradiol, AMPK and thermogenesis
Estradiol also affects weight regulation by impacting
thermogenesis. Thermogenesisisthedissipationofenergy
through heat production. This increased energy expenditure
contributes to weight loss. Thermogenesis may occur through
both shivering and non-shivering mechanisms (94). Brown
adipose tissue (BAT) is a specialized fat depot characterized by
increased energy expenditure and heat production (95). Its
expansion and/or activation can protect against diet-induced
obesity. The classical thermogenesis pathway revolves around
the sympathetic nervous system-catecholamine-uncoupling
protein 1 axis. UCP1 is a proton channel which allows
dissipation of the proton gradient across the mitochondrial
matrix, without adenosine triphosphate (ATP) production.
This dissipation generates energy in the form of heat.
Activation of the sympathetic nervous system (SNS) releases
catecholamines (e.g. norepinephrine) which increase UCP1
activity. Centrally, several hypothalamic regions, most
especially the ventromedial hypothalamus (VMH), are known
to regulate this pathway. Electrical or pharmacological
stimulation of this nucleus increases BAT thermogenesis (96–
101). Estradiol modulates thermogenesis at three points on this
VMH-SNS-BAT pathway: 1) through its effects on the VMH
nucleus 2) through its effects on SNS signaling 3) directly
through its effects on BAT.
Within the VMH nucleus, AMP-activated protein kinase
(AMPK) appears to be a key mediator of estradiol’s effects.
AMPK is a so-called ‘cellular energy sensor’(102,103). It senses
the ADP:ATP and AMP:ATP ratios and alters ATP production
as a cell requires (104). AMPK activation in the VMH decreases
energy expenditure (105–107) and AMPK inhibition increases
energy expenditure (Figure 1). Animal models have shown that
estradiol increases energy expenditure through increased
thermogenesis and lipolysis of BAT. Estradiol-induced BAT
thermogenesis and its consequent body weight loss can be
prevented by activation of AMPK in the VMH (108). This
suggests that estradiol may increase thermogenesis by the
inhibiting AMPK at the VMH nucleus of the hypothalamus.
AMPK also acts as an important mediator for other peripheral
modulators of thermogenesis (109). Such modulators include
thyroid hormone, GLP-1, and leptin (109,110). AMPK may also
mediate other effects of estrogens, e.g. on glucose
homeostasis (111).
Estradiol acts at the second point of the VMH-SNS-BAT
pathway by increasing norepinephrine turnover, thus increasing
non-shivering thermogenesis (112,113). It also acts on BAT
tissue directly, though interestingly not on UCP1 (114–116).
It is important to mention that BAT is a specialized fat depot
characterized by increased energy expenditure and heat
production (95). Its expansion and/or activation can protect
against diet-induced obesity. Beige adipocytes that share some
common characteristics with brown adipocytes such as high
mitochondria content and uncoupling protein 1 (UCP1)
expression can be induced in white adipose tissue (WAT).
This process is called WAT browning (117).
Interactions between estrogens and
peripheral feedback signals
controlling appetite
Thus far we have considered estradiol’s direct effects on the
central control of appetite. Estradiol’s central effects on appetite
are also modulated by a number of other peripheral signals
(Figure 1). These signals include peptides secreted by the
gastrointestinal tract (CCK, GLP-1), the pancreas (glucagon
and insulin) and adipose tissue (leptin).
CCK interaction with estradiol in
satiety control
Cholecystokinin (CCK) is a key controller of meal-ending
satiation in animals and humans (118–121). CCK is particularly
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known for its local effects in the gastrointestinal system. It is
produced by cells lining the duodenum and its name derives
from its effect on the gallbladder, causing it to contract and
release bile into the intestine. However, further work has since
revealed that CCK is also important for satiety. Indeed, CCK has
moved from being considered a local gut hormone, to being
recognized as an almost ubiquitous chemical messenger (122).
We will consider its effect on peripheral and central satiety
control mechanisms.
Peripherally administered CCK reduces food intake (123).
This effect is mediated by the vagus nerve. CCK increases vagal
excitability (124–127). The vagus in turn stimulates second order
neurons in the NST (128,129), located in the medulla of the
brainstem (Figure 1). NST plays a key role in appetite. This is
perhaps unsurprising given that it integrates gustatory and
visceral input from cranial nerves VII, IX, and X (130). The
NST, in turn, signals to a number of other brain centres that
impact satiety. In summary, CCK activates vagal fibres, which in
turn activate NST neurons, inducing a feeling of satiety.
Evidence for estradiol’s interaction with CCK comes from
studies of ovariectomized rats. In ovariectomized rats,
subcutaneous replacement of estradiol potentiates suppression
of total food intake induced by CCK (22,131,132). Furthermore,
estradiol potentiates endogenous CCK-induced suppression of
food intake in both hormone-replaced ovariectomized and
estrous control females (133–136). Estradiol modulates vagal
nerve reactivity and NST activity. In ovariectomized rats,
replacement of estradiol in this nucleus reduces food intake
and this effect is blunted by co-administration of an ERa
antagonist (137,138). Estradiol augments the density of axonal
projections and the excitability of vagal afferent neurons (139).
The sensitivity of the vagal nerve to estradiol fluctuates through
the estrous cycle, as ERaexpression changes in response to
circulating estradiol levels (140).
Thus far, we have focused on peripherally produced CCK.
However, as previously indicated, CCK is now known to be
produced almost ubiquitously, including in the brain. CCK
producing neurons are known to be important for appetite
control. Estradiol has been shown to impact this central CCK
expression. For example, administering physiological doses of
estradiol dramatically increases CCK mRNA levels in the
posterodorsal medial amygdaloid nucleus (MeApd) and in the
central part of the mPOA. These regions are part of the limbic-
hypothalamic circuit (141). There is evidence to suggest that, as
in the NST, CCK and estradiol also act synergistically in the
limbic-hypothalamic circuit. This is indicated by CCK
expression in pertinent brain regions (e.g. hypothalamus)
changing with estrous cycle phase in rats. Specifically, CCK
expression is highest during the pro-estrous phase when plasma
estradiol levels are at their highest (132,133,142). Taken
together, it is likely that estradiol’s anorexigenic effects are due
not only to estradiol’s direct effects on appetite, but also due to its
interaction with other molecules, such as CCK.
Leptin
Leptin is an adipocyte-derived hormone that reflects energy
storage (143). In normal conditions, leptin prevents body weight
gain by suppressing feeding (144,145) and increasing energy
expenditure (146–148). In general, leptin down-regulates
orexigenic peptides, and up-regulates anorexigenic peptides,
leading to a reduction in food intake. In particular, leptin
modulates the signals for satiety found in the ARC. For
example, when leptin levels are reduced, POMC expression is
also reduced and NPY expression is increased (149).
Furthermore, as mentioned, POMC is a precursor for a-MSH,
which helps control appetite. a-MSH antagonists antagonize
leptin’s anorexigenic effect (150). It must be remembered that
estradiol exerts some of its direct effects on satiety through these
same neuronal populations. Interestingly, both estradiol and
leptin receptors colocalize in kisspeptinergic neurons, which are
considered to be the link between nutrition (metabolism) and
reproduction (ovulatory function) (151).
These neurons are present in the ARC, VMH, and POA
(152). Such co-localization raises the question: might leptin and
estradiol interact centrally? The answer appears to be yes. In the
pro-estrous (high estradiol) phase of the estrous cycle, estradiol
increases leptin mRNA expression and serum leptin levels (153).
Furthermore, it has been shown that physiological high estradiol
levels correlate with increased leptin sensitivity and that reduced
leptin sensitivity after oophorectomy can be restored with
estrogen treatment (154). Deletion of leptin receptors in vagal
afferent neurons disrupts estrogen signaling, body weight, food
intake and hormonal controls of feeding in female mice (140).
Thus, estradiol and leptin interact to inhibit nutrient uptake.
Clinically, it is interesting to consider how this may alter the
usual pattern of cyclical feeding changes in obese women. Leptin
resistance, commonly found in obese women, is likely to blunt
the peri-ovulatory anorexigenic effect of estradiol. It is already
known that leptin resistance also disrupts ovulatory function by
inhibiting the kisspeptinergic system (151). This ovulatory
dysfunction leads to abnormal estradiol values, thus likely
further affecting physiological body weight regulation.
Insulin
Insulin affects energy balance regulation (155). Basal plasma
insulin concentrations are proportional to body adiposity (156).
Insulin’s secretion and synthesis are affected by a number of
genetic, environmental and epigenetic factors. For example,
dietary choices impact insulin secretion and synthesis (157).
Insulin, like leptin, stimulates anorexigenic pathways, thereby
causing reduced food intake. Insulin receptors are expressed on
hypothalamic neurons, predominantly in ARC (158). Insulin
affects appetite by reducing the expression of NPY neurons in
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the ARC (159). Again, this is where estradiol also exerts a
number of direct effects on appetite, thus raising the possibility
of estradiol-insulin interactions to alter food intake.
Furthermore, estradiol and insulin are thought to interact at
the peripheral level. For example, estradiol may protect against
the development of metabolic syndrome by impacting insulin
sensitivity. The post-menopausal drop in estradiol levels is
thought to explain, at least partially, the increase in metabolic
disorders in post-menopausal women (160–163). In support of
this hypothesis, hormone replacement therapies (HRT) that
include estradiol have been shown to improve insulin
sensitivity and lower blood glucose levels (164–166). This
improvement in insulin sensitivity reduces the incidence of
diabetes in postmenopausal women (167–169). Support for
estradiol altering insulin sensitivity has also been reported in
rodents, since estradiol deficient animals are more likely to
develop insulin resistance (170,171).
The clinical implications of this interaction extend beyond
hypo-estrogenic states (e.g. post-menopause). A number of
women have a hyper-estrogenic state. This can be as a
consequence of endocrinopathies (such as PCOS) or simply of
their life stage (e.g. perimenopause). Supra-physiological
concentrations of estradiol induce a decrease in the expression
of insulin receptors, thereby contributing to the development of
insulin resistance (172,173). High doses of estradiol also
significantly decrease the amount of insulin receptors and the
insulin receptor substrate 1 (IRS-1) levels in muscle and adipose
tissue in vitro (174). These changes induce a greater release of
intracellular calcium given the high concentrations of estradiol,
inducing a greater release of insulin into the bloodstream,
contributing to sustained hyperinsulinemia. Over time, insulin
resistance contributes to the development of obesity, diabetes
and cardiovascular diseases, and sustained hyperinsulinemia
contributes to the generation and/or maintenance of ovulatory
dysfunction (175,176).
Overall, this evidence suggests that abnormally high or low
levels of estradiol can both lead increased insulin resistance in
the brain and peripheral tissues. This means that insulin
resistance may be more likely to develop during hyper-
estrogenic periods of a woman’s life. Such periods include
adolescence, pregnancy and the perimenopause. Women could
be more at risk of weight gain during these stages.
GLP-1
GLP-1 is secreted by the pancreas and by intestinal L-cells in
response to glucose-induced insulin release (177,178). It also
reduces glucagon secretion in response to a nutrient load (179).
Whilst it has a paracrine or endocrine role in the periphery,
centrally GLP-1 is an important neuroendocrine agent. GLP-1 is
produced in various brain regions including the hypothalamus,
the hippocampus, the hindbrain, and the mesolimbic system
(180). Both human and animal studies have demonstrated that
GLP-1 contributes to the physiological control of appetite and
meal size (108,181–186). Suppression of GLP-1R expression in
NST neurons in animal models causes an increase in food intake
due to an increase in meal size (187). By contrast, central
injections GLP-1R agonists cause a reduction in food intake
(188). This anorexic response is largely mediated by neuronal
areas within the hypothalamus and brainstem (189–193). Many
of these areas are also the ones where estradiol acts to control
appetite (194–197). As mentioned earlier, estradiol impacts
vagal nerve fiber excitability and density. In the same way,
GLP-1R expression in vagal afferent neurons has also been
found to be important for affecting food intake and meal size
(198). Such co-localization in the sites of GLP and estradiol
activity raises the possibility of estradiol and GLP-1 interacting
to alter food intake. Support for this hypothesis comes from the
finding that, in ovariectomized rats, estradiol replacement
enhances peripheral GLP-1 induced suppression on food
intake (199,200).
Estradiol, brain insulin sensitivity
and resistance
The activation of estrogenic pathways exerts a
neuroprotective effect in the CNS through four different
mechanisms [reviewed in (53)]. Low estradiol values may be
foundinobesewomenwithovulatorydysfunctionandin
women during the peri-menopausal and post-menopausal
periods. This means that such women lose the neuroprotective
effect of estradiol. Briefly, estradiol improves neuronal
survival through:
1. Activation of anti-apoptotic and cell survival pathways
(90,201). Estradiol promotes anti-apoptotic pathways
by enhancing the transcription of anti-apoptotic genes
such as B-cell lymphoma 2 (BCL2) (202)and
inactivating pro-apoptotic proteins such as BAD
(BCL2 associated agonist of cell death) (203,204).
2. Regulation of bioenergetics systems. Estradiol increases
glucose availability and ATP production in neuronal
mitochondria (205). It does this by increasing the
number of glucose transporters, glucose uptake and
the activity of glycolytic enzymes in aerobic glycolysis
(201). It also helps ensure neurons meet their high
energy demands appropriately.
3. Regulation of neurogenesis. Estradiol stimulates
proliferation of neural progenitor cells in a time- and
dose-dependent manner (201,206).
4. Increased cell survival through protection against free-
radical damage. Estradiol reduces oxidative damage and
its consequent apoptotic process (205).
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Mitochondria are commonly considered the cellular
powerhouse sustaining life. Mitochondria produce ATP,
enabling stress adaptation for survival. During the production
of ATP, the transport of electrons generates reactive oxygen
species (ROS) that damage macromolecules, such as
mitochondrial DNA, proteins and lipids. This macromolecular
damage can contribute to mitochondrial stress. Estradiol
regulates mitochondrial morphology and function (207).
Estrogens and androgens protect mitochondria against the
degenerative effects that occur with aging (208). Estradiol
inhibits the activation of cell death caused by ROS (209).
When estradiol levels start to decline as women age or they
transit to menopause, the protective effect of estradiol is lost
(210). As a consequence, when estradiol levels are reduced, ROS
levels increase and cause mitochondrial dysfunction.
Mitochondrial dysfunction is associated with an imbalance
between pro- and anti-oxidants (210). As this dysfunction
worsens, significant mitochondrial damage can occur. This
damage triggers tissue events associated with cellular
senescence as loss of replicative capacity. In the brain,
neuronal damage and alteration of cognitive processes occur.
Mitochondrial dysfunction occurs in all individuals with age
(211). However, the post-menopausal drop in estradiol levels
exacerbates this mitochondrial dysfunction. Sex hormone
treatment during menopause transition helps reverse the
deleterious effects of the drop in estradiol (212).
Insulin also has neuroprotective effects. Insulin action has
been found to improve visual and spatial episodic memory,
working memory, declarative memory, and learning processes
(reviewed in (16)). The neuronal mitochondrial dysfunction that
follows a drop in estradiol levels in women causes insulin
insensitivity and eventually brain insulin resistance to develop
(16,213,214).
A proper brain insulin action has been shown to improve
mood and counteract cognitive dysfunction in dementia (215).
Patients with chronic diabetes are more likely to suffer cognitive
impairment, and a number of neurodegenerative disorders,
including Alzheimer´s Disease (AD), Parkinson’s Disease and
other forms of dementia. All these disorders share the following
pathophysiological features: amyloid baccumulation, tau
hyperphosphorylation, cerebral vasculopathy, inflammation,
and oxidative stress in the CNS. These features are indicative
of impaired insulin sensitivity in neurons and glial cells (15,216–
218). The term “Type III diabetes”has been proposed to describe
AD that may develop from glucose and insulin dysregulation at
the CNS (213,219).
Finally, is important to highlight that physiological brain
insulin sensitivity has also been identified as a predictor of
successful weight loss (220). Evidence shows that a high
cerebral sensitivity to insulin is related to weight loss (220).
Conversely, cerebral insulin resistance leads to increased body
weight and obesity. Reduced cerebral insulin sensitivity disrupts
the neural controlling food intake. This result in overeating and
weight gain (221).
GLP-1 analogs and weight
regulation
Weight control is key to combatting obesity and T2D. Recently,
attention has turned to using GLP-1 analogs, or GLP-1/glucagon
co-agonism to treat these disorders [for review see (222–228)]. For
example, liraglutide is a once-daily, subcutaneously administered,
GLP-1 receptor agonist (229–232). Results obtained from clinical
trials show that it can aid weight loss (229,230,233). Indeed, a
meta-analysis suggested that GLP-1 agonists may improve weight
loss and insulin resistance in obese/overweight women than
metformin does (234). Liraglutide has both peripheral and central
effects. Peripherally, liraglutide delays gastric emptying, thus
increasing the production of other peripheral satiety signals (235).
Central administration of liraglutide in laboratory studies results in
weight loss through decreased food intake (188,236). This is
mediated by the ARC, PVH, and LH hypothalamic nuclei (188,
236). Liraglutide action in the VMH also increases thermogenesis
by increasing UCP1 expression in BAT and WAT (white adipose
tissue) (188). Like estradiol, liraglutide inhibits AMPK activity in
VMH neurons (188) and alters SNS activity as part of the VMH-
SNS-BAT pathway. This is shown by the fact that catecholamine
(specifically b3-AR) antagonists block the liraglutide-induced
increase in UCP1 levels in BAT and WAT (188,236).
Estrogens for weight control
Post-menopause, women tend to gain weight. This weight
gain is often attributed to aging in general as well as to hormonal
changes. As discussed earlier, estradiol levels affect
mitochondria. Mitochondria are considered to be the cellular
‘hub’of aging (210). Estradiol receptors are located in both the
inner and outer mitochondrial membranes, as well as in the cell
plasma membrane, cell cytoplasm and nucleus (209). The
menopausal drop in estradiol will thus affect the process of
ATP synthesis and so will alter cellular metabolic pathways.
Mitochondrial dysfunction will induce cellular senescence, most
especially in brain, adipose and muscle tissues, thus affecting
cellular metabolic control, fat distribution and weight gain.
In premenopausal women, there is significant interest in
whether supra-physiological concentrations of estradiol, as
found in combined hormonal contraceptives (CHC), impact
women’s weight (237). This is complicated by the fact that
combined contraceptives contain not only estrogens, but also
progestins. Thus far, a 2014 Cochrane review found that there
was insufficient evidence to determine the effect of CHCs on
weight (237). The review found only four trials comparing CHCs
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Frontiers in Endocrinology frontiersin.org08
with placebo, of which only one followed patients for over a year
(238), whilst the remaining three followed weight changes over
only 6-9 cycles. A review in which progestin-only contraceptives
were studied highlighted the importance of the follow-up period,
since longer follow-up periods (2-3 years) showed twice the
degree of weight gain as compared to shorter studies (1 year)
(239). Thus, the Cochrane review may have been somewhat
limited by not just the number of women studied but the
duration of clinical trials.
In the post-menopausal population, a 2005 Cochrane review
found no effect of estradiol (opposed or unopposed) on women´
s weight (240). However, since this review, a subsequent study
(KEEPS study) found that BMI increased significantly less (by
1.09kg/m
2
) in women on HRT rather than placebo (241,242).
Such findings are in keeping with a 2009 HRT study (243)
finding that women randomized to HRT gained less weight than
those on placebo.
The evidence shown above reinforces the fact that estradiol
as a main regulator of mitochondrial function would be an
essential factor for healthy weight maintenance in women.
GLP-1 and estradiol conjugates
Estradiol and GLP-1 conjugates share many effects and
common pathways in weight control (244). Laboratory studies
investigating a potential synergistic interaction between estradiol
and GLP-1 have given inconsistent results. One study showed
little synergy between exogenously administered labile estradiol-
GLP-1 conjugates (245). However, another study noted sex-
differences, which could be related to sex steroid levels, in the
response to GLP-1 agonists (246). The main differences in GLP-
1 activity that have been found between males and females are: i)
increased weight loss caused by the GLP-1 agonist, liraglutide, in
women as compared with men (247); ii) more immediate
increases in GLP-1 levels immediately post-exercise in women
during the follicular-phase than in men (248) and iii) increased
reward circuits activation following GLP-1 administration in
female rats as compared to male rats. Further work is needed to
investigate whether it is estradiol that mediates these sex
differences in GLP-1 activity. Endogenous GLP-1 levels have
been shown to be lower in the follicular phase compared with the
luteal phase (27). This is thought to be due to slower gastric
emptying during the follicular phase (27). The luteal phase of the
menstrual cycle has higher levels of estradiol and progesterone.
It would be interesting to observe whether exogenous GLP-1 is
more efficacious in women when administered during this
hormonal phase as compared with the follicular phase. If so,
then perhaps therapeutic GLP-1 could be given more
infrequently, but synchronized to women’s hormonal cycles.
Concomitant use of GLP-1 and estradiol conjugates has been
primarily limited by the oncogenic and gynecological side-effects
that have been attributed to estrogens. Furthermore, weight loss
associated with GLP-1 administration alone often fails to meet
the required weight reduction for a particular woman (249).
Recently, researchers have attempted to circumvent such
shortcomings through unimolecular polypharmacy. For
example, Finan et al have developed a stable GLP-1-estradiol
conjugate (245). They found that a stable GLP-1-estradiol
conjugate caused greater weight loss in obese male mice than
either GLP-1 controls or labile GLP-1-estradiol conjugates. In
labile conjugates, the estradiol rapidly disseminates throughout
the circulation in an untargeted fashion. Thus, conjugation
appears key to improving GLP-1 and estradiol synergistic
effects on weight. The weight loss achieved through the stable
conjugate was mainly due to appetite suppression and a decrease
in food-intake. Glycemic control and insulin sensitivity were
also improved.
Promisingly, this conjugate did not have off-target effects in
female mice. Neither the GLP-1 control nor the stable conjugate
resulted in an increased uterine weight in ovariectomized mice.
This finding indicates that side effects as endometrial hyperplasia
would not be expected if administered to women. By contrast,
the labile conjugate, which rapidly degrades to release estradiol,
did result in increased uterine weight, suggesting off-target
effects. Furthermore, LH and FSH levels in mice treated with
the GLP-1-estradiol conjugate were unchanged. Thus, the
conjugate did not appear to interfere with the hypothalamic-
pituitary-gonadal axis.
The authors suggest that the GLP-1-estradiol compound
allows targeted delivery of estradiol to the CNS. Thus, conjugate
estradiol delivery differs significantly from peripheral
administration of estradiol as in HRT for example. Indeed,
when mice lacking GLP-1 receptors in the CNS were given the
GLP-1-estradiol analogue, weight loss was equivalent only to
that of GLP-1 administered peripherally. The conjugate also had
beneficial effects on glucose homeostasis. This could be due to an
additional effect on hepatic glucose production (245).
Furthermore, in New Zealand obese mice, the GLP-1-estradiol
conjugate protects against carbohydrate-induced hyperglycemia
(250). This was largely due to it causing a reduction in appetite,
mediated by an induction of POMC expression. Although
peripheral effects of the estradiol-GLP-1 conjugates are
anticipated, most evidence suggests that the conjugate acts
centrally to suppress food-reward (250). These proof-of-
concept studies raise interesting possibilities for therapeutic
strategies in humans. There is no research, to the authors’
knowledge, investigating GLP-1 analogs in the postmenopausal
population specifically. However, in a recent meta-analysis
showing the beneficial effects of GLP-1 analogs on weight loss,
over 57% of participants were female, and the median age at
randomization was 55 years (233). Given that the average age at
menopause is 51 years, it is highly likely that a significant
number of participants were peri- or post-menopausal women.
Furthermore, given that other anti-diabetic treatments such as
SGLT-2 inhibitors are feared to adversely affect bone health,
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Frontiers in Endocrinology frontiersin.org09
there is increasing interest in the benefits of GLP-1 analogs for
diabetic post-menopausal women (251). Given the
neuroprotective effects of both GLP-1 and estradiol, it would
also be interesting to know how such agents might reduce
neurodegeneration, especially in menopausal women.
Conclusions and future directions
Obesity in women is a global problem. The comorbidities
associated with it decrease their quality and life expectancy.
Estradiol is crucial not only in reproductive function, but for the
regulation of body weight. It has been showed that normal peri-
ovulatory estradiol concentrations have anorexigenic effects.
Conversely, stages of a woman’s life, such as adolescence,
perimenopause and menopause, that are associated with
reduced estradiol, are also associated with weight gain.
Conditions, such as pregnancy, in which estradiol levels are
high, are a high-risk time where susceptible women are more at
risk of developing metabolic comorbidities such as obesity and
gestational diabetes. Furthermore, ovulatory dysfunction, such
as occurs in PCOS, is associated with weight gain and insulin
resistance. Estradiol regulates body weight by decreasing
appetite and increasing feelings of satiety. Estradiol controls
appetite by acting at specific hypothalamic nuclei, such as the
ARC or LH. Estradiol also interacts with peripherally
synthetized peptides, such as CCK, leptin and insulin. One of
these mediators, GLP-1, acts similarly to and, potentially,
synergistically with estradiol. Although GLP-1 analogs were
initially characterized as antidiabetic agents, they are
increasingly being recognized as anti-obesity agents. The
reductioninweightgainwhenGLP-1analogsare
administered is partially explained by their effects on the CNS.
The synergistic effects of GLP-1 analogs combined with estradiol
conjugates are promising. If translated to human studies, such
conjugates could help women to maintain a healthy body weight
and preserve their mental function. This could be particularly
important for women whose estradiol levels are abnormal,
perhaps as a result of ovarian dysfunction, or whose estradiol
levels drop, as part of the normal estradiol decline during
menopause. GLP-1-estradiol analogues could perhaps be used
in the future to improve central insulin sensitivity. As
central insulin resistance appears to be a risk factor for
neurodegenerative disorders, these analogues might provide
interesting avenues to protect against neurodegeneration and
conditions such as Alzheimer’s and Parkinson’sdisease.
Considering the above, future lines of research should focus
on the proper dose, timing, safety and frequency when
administering GLP-1 analogs and conjugated estradiol as a
treatment for body weight disorders.
Author contributions
PV, JM, GP, and JDR: bibliographic search, writing, review
and/or revision of the manuscript. All authors contributed to the
article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
References
1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity and
severe obesity among adults: United states, 2017-2018. NCHS Data Brief (2020)
360):1–8. Available at: https://www.cdc.gov/nchs/products/index.htm.
2. Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, et al. European
Guidelines for obesity management in adults. Obes Facts (2015) 8(6):402–24. doi:
10.1159/000442721
3. Gambineri A, Laudisio D, Marocco C, Radellini S, Colao A, Savastano S.
Female infertility: which role for obesity? Int J Obes Suppl (2019) 9(1):65–72.
doi: 10.1038/s41367-019-0009-1
4. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among
adults and youth: United states, 2015–2016. In: NCHS data brief, no 288, vol. 288).
Hyattsville, MD: National Center for Health Statistics. NCHS Data Brief (2017).
p. 1–8. Available at: https://www.cdc.gov/nchs/data/databriefs/db288.pdf.
5. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence
and phenotypic features of polycystic ovary syndrome: A systematic review and
meta-analysis. Hum Reprod (2016) 31(12):2841–55. doi: 10.1093/humrep/dew218
6. Naz SG, Tehrani, Ramezani F, Alavi Majd H, Ahmadi F. The prevalence of
polycystic ovary syndrome in adolescents: A systematic review and meta-analysis.
Int J Reprod Biomed (2019) 17(8):533–42. doi: 10.18502/ijrm.v17i8.4818
7. Silvestris E, de Pergola G, Rosania R, Loverro G. Obesity as disruptor of the
female fertility. Reprod Biol Endocrinol (2018) 16(1):1–13. doi: 10.1186/s12958-
018-0336-z
Vigil et al. 10.3389/fendo.2022.951186
Frontiers in Endocrinology frontiersin.org10
8. Liu T, Qin QY, Qu JX, Wang HY, Yan J. Where are the theca cells from: The
mechanism of theca cells derivation and differentiation. Chin Med J (Engl) (2020)
133(14):1711–8. doi: 10.1097/CM9.0000000000000850
9. Vigil P, Cortes M, del Rio MJ, Godoy A. Sindrome de ovario poliquistico. In:
Guzman E, Lalonde A, editors. Seleccion de temas en ginecoobstetricia, Santiago,
Chile: Publimpacto (2007). p. 563–78.
10. Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado AM, Cortes ME.
Evidence of subpopulations with different levels of insulin resistance in women
with polycystic ovary syndrome. Hum Reprod (2007) 22(11):2974–80. doi: 10.1093/
humrep/dem302
11. Geary N, Asarian L. Modulation of appetite by gonadal steroid hormones.
Philos Trans R Soc B Biol Sci (2006) 361(1471):1251–63. doi: 10.1098/
rstb.2006.1860
12. Hirschberg AL. Sex hormones, appetite and eating behaviour in women.
Maturitas (2012) 71(3):248–56. doi: 10.1016/j.maturitas.2011.12.016
13. Leeners B, Geary N, Tobler PN, Asarian L. Ovarian hormones and obesity.
Hum Reprod Update (2017) 23(3):300–21. doi: 10.1093/humupd/dmw045
14. Xu Y, Lopez M. Central regulation of energy metabolism by estrogens. Mol
Metab (2018) 15:104–15. doi: 10.1016/j.molmet.2018.05.012
15. Tumminia A, Vinciguerra F, Parisi M, Frittitta L. Type 2 diabetes mellitus
and alzheimer’s disease: Role of insulin signalling and therapeutic implications. Int
J Mol Sci (2018) 19(11):1–17. doi: 10.3390/ijms19113306
16. Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring HU.
Brain insulin resistance at the crossroads of metabolic and cognitive disorders in
humans. Physiol Rev (2016) 96(4):1169–209. doi: 10.1152/physrev.00032.2015
17. Hölscher C. Central effects of GLP-1: New opportunities for treatments of
neurodegenerative diseases. J Endocrinol (2014) 221(1):T31–T41. doi: 10.1530/
JOE-13-0221
18. McClean PL, Hölscher C. Liraglutide can reverse memory impairment,
synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of alzheimer’s
disease. Neuropharmacology (2014) 76(PART A):57–67. doi: 10.1016/
j.neuropharm.2013.08.005
19. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-
regulating pathways in the hypothalamic regulation of body weight. Endocr Rev
(1999) 20(1):68–100. doi: 10.1210/edrv.20.1.0357
20. Williams G, Bing C, Cai XJ, Harrold JA, King PJ, Liu XH. The hypothalamus
and the control of energy homeostasis: Different circuits, different purposes. Physiol
Behav (2001) 74(4–5):683–701. doi: 10.1016/S0031-9384(01)00612-6
21. Davidsen L, Vistisen B, Astrup A. Impact of the menstrual cycle on
determinants of energy balance: A putative role in weight loss attempts. Int J
Obes (2007) 31(12):1777–85. doi: 10.1038/sj.ijo.0803699
22. Butera PC, Bradway DM, Cataldo NJ. Modulation of the satiety effect of
cholecystokinin by estradiol. Physiol Behav (1993) 53(6):1235–8. doi: 10.1016/
0031-9384(93)90387-U
23. Eckel LA. Estradiol: A rhythmic, inhibitory, indirect control of meal size.
Physiol Behav (2004) 82(1):35–41. doi: 10.1016/j.physbeh.2004.04.023
24. Dye L, Blundell JE. Menstrual cycle and appetite control: Implications for
weight regulation. Hum Reprod (1997) 12(6):1142–51. doi: 10.1093/humrep/
12.6.1142
25. van Vugt DA. Brain imaging studies of appetite in the context of obesity and
the menstrual cycle. Hum Reprod Update (2009) 16(3):276–92. doi: 10.1093/
humupd/dmp051
26. Pohle-Krauza RJ, Carey KH, Pelkman CL. Dietary restraint and menstrual
cycle phase modulated l-phenylalanine-induced satiety. Physiol Behav (2008) 93(4–
5):851–61. doi: 10.1016/j.physbeh.2007.11.051
27. Brennan IM, Feltrin KL, Nair NS, Hausken T, Little TJ, Gentilcore D, et al.
Effects of the phases of the menstrual cycle on gastric emptying, glycemia, plasma
GLP-1 and insulin, and energy intake in healthy lean women. Am J Physiol -
Gastrointest Liver Physiol (2009) 297(3):602–10. doi: 10.1152/ajpgi.00051.2009
28. Hill AJ, Heaton-Brown L. The experience of food craving: A prospective
investigation in healthy women. J Psychosom Res (1994) 38(8):801–14. doi:
10.1016/0022-3999(94)90068-X
29. Bowen DJ, Grunberg NE. Variations in food preference and consumption
across the menstrual cycle. Physiol Behav (1990) 47(2):287–91. doi: 10.1016/0031-
9384(90)90144-S
30. Cohen IT, Sherwin BB, Fleming AS. Food cravings, mood, and the
menstrual cycle. Horm Behav (1987) 21(4):457–70. doi: 10.1016/0018-506X(87)
90004-3
31. Dalvit-McPhillips SP. The effect of the human menstrual cycle on nutrient
intake. Physiol Behav (1983) 31(2):209–12. doi: 10.1016/0031-9384(83)90120-8
32. Johnson WG, Corrigan SA, Lemmon CR, Bergeron KB, Crusco AH. Energy
regulation over the menstrual cycle. Physiol Behav (1994) 56(3):523–7. doi:
10.1016/0031-9384(94)90296-8
33. Barr SI, Janelle KC, Prior JC. Energy intakes are higher during the luteal
phase of ovulatory menstrual cycles. Am J Clin Nutr (1995) 61(1):39–43. doi:
10.1093/ajcn/61.1.39
34. Martini MC, Lampe JW, Slavin JL, Kurzer MS. Effect of the menstrual cycle
on energy and nutrient intake. Am J Clin Nutr (1994) 60(6):895–9. doi: 10.1093/
ajcn/60.6.895
35. Cross GB, Marley J, Miles H, Willson K. Changes in nutrient intake during
the menstrual cycle of overweight women with premenstrual syndrome. Br J Nutr
(2001) 85(4):475–82. doi: 10.1079/BJN2000283
36. Wurtman JJ, Brzezinski A, Wurtman RJ, Laferrere B. Effect of nutrient
intake on premenstrual depression. Am J Obstet Gynecol (1989) 161(5):1228–34.
doi: 10.1016/0002-9378(89)90671-6
37. Pliner P, Fleming AS. Food intake, body weight, and sweetness preferences
over the menstrual cycle in humans. Physiol Behav (1983) 30(4):663–6. doi:
10.1016/0031-9384(83)90240-8
38. Brzez1nski AA, Wurtman JJ, Wurtman RJ, Gleason R, Greenfield J, Nader
T. D-fenfluramine suppresses the increased calorie and carbohydrate intakes and
improves the mood of women with premenstrual depression. Obstet Gynecol
(1990) 76(2):296–301. doi: 10.1016/0020-7292(91)90645-l
39. Lundman B, Asplund K, Norberg A. Metabolic control, food intake and
mood during the menstrual cycle in patients with insulin-dependent diabetes. Int J
Nurs Stud (1994) 31(4):391–401. doi: 10.1016/0020-7489(94)90079-5
40. Piers LS, Diggavi SN, Rijskamp J, Van Raaij JMA, Shetty PS, Hautvast JGAJ.
Resting metabolic rate and thermic effect of a meal in the follicular and luteal
phases of the menstrual cycle in well-nourished Indian women. Am J Clin Nutr
(1995) 61(2):296–302. doi: 10.1093/ajcn/61.2.296
41. Bryant M, Truesdale KP, Dye L. Modest changes in dietary intake across the
menstrual cycle: Implications for food intake research. Br J Nutr (2006) 96(5):888–
94. doi: 10.1017/BJN20061931
42. Fong AKH, Kretsch MJ. Changes in dietary intake, urinary nitrogen, and
urinary volume across the menstrual cycle. Am J Clin Nutr (1993) 57(1):43–6. doi:
10.1093/ajcn/57.1.43
43. Gorczyca AM, Sjaarda LA, Mitchell EM. Changes in macronutrient,
micronutrient, and food group intakes throughout the menstrual cycle in
healthy, premenopausal women. Eur J Nutr (2016) 55(3):1181–8. doi: 10.1007/
s00394-015-0931-0
44. Derntl B, Schöpf V, Kollndorfer K, Lanzenberger R. Menstrual cycle phase
and duration of oral contraception intake affect olfactory perception. Chem Senses
(2013) 38(1):67–75. doi: 10.1093/chemse/bjs084
45. Alonso-Alonso M, Ziemke F, Magkos F, Barrios FA, Brinkoetter M, Boyd I,
et al. Brain responses to food images during the early and late follicular phase of the
menstrual cycle in healthy young women: Relation to fasting and feeding. Am J Clin
Nutr (2011) 94(2):377–84. doi: 10.3945/ajcn.110.010736
46. Alberti-Fidanza A, Fruttini D, Servili M. Gustatory and food habit changes
during the menstrual cycle. Int J Vitam Nutr Res (1998) 68(2):149–53. doi: 10.1038/
sj.ejcn.1600654
47. Navarrete-Palacios E, Hudson R, Reyes-Guerrero G, Guevara-GuzmanR.
Lower olfactory threshold during the ovulatory phase of the menstrual cycle. Biol
Psychol (2003) 63(3):269–79. doi: 10.1016/S0301-0511(03)00076-0
48. Than TT, Delay ER, Maier ME. Sucrose threshold variation during the
menstrual cycle. Physiol Behav (1994) 56(2):237–9. doi: 10.1016/0031-9384(94)
90189-9
49. Pletzer B, Crone JS, Kronbichler M, Kerschbaum H. Menstrual cycle and
hormonal contraceptive-dependent changes in intrinsic connectivity of resting-
state brain networks correspond to behavioral changes due to hormonal status.
Brain Connect (2016) 6(7):572–85. doi: 10.1089/brain.2015.0407
50. Dreher JC, Schmidt PJ, Kohn P, Furman D, Rubinow D, Berman KF.
Menstrual cycle phase modulates reward-related neural function in women. Proc
Natl Acad Sci U S A (2007) 104(7):2465–70. doi: 10.1073/pnas.0605569104
51. Frank TC, Kim GL, Krzemien A, Van Vugt DA. Effect of menstrual cycle
phase on corticolimbic brain activation by visual food cues. Brain Res (2010)
1363:81–92. doi: 10.1016/j.brainres.2010.09.071
52. Caruso S, Grillo C, Agnello C, Maiolino L, Intelisano G, Serra A. A
prospective study evidencing rhinomanometric and olfactometric outcomes in
women taking oral contraceptives. Hum Reprod (2001) 16(11):2288–94. doi:
10.1093/humrep/16.11.2288
53. Del Rı
o JP, Alliende MI, Molina N, Serrano FG, Molina S, Vigil P. Steroid
hormones and their action in women’s brains: The importance of hormonal
balance. Front Public Heal (2018) 6:1–15. doi: 10.3389/fpubh.2018.00141
54. Klump KL, Keel PK, Culbert KM. Ovarian hormones and binge eating:
exploring associations in community samples. Psychol Med (2008) 38(12):1749–57.
doi: 10.1017/S0033291708002997
55. Edler C, Lipson SF, Keel PK. Ovarian hormones and binge eating in bulimia
nervosa. Psychol Med (2007) 37(1):131–41. doi: 10.1017/S0033291706008956
Vigil et al. 10.3389/fendo.2022.951186
Frontiers in Endocrinology frontiersin.org11
56. Klump KL, Keel PK, Sisk C, Burt SA. Preliminary evidence that estradiol
moderates genetic influences on disordered eating attitudes and behaviors during
puberty. Psychol Med (2010) 40(10):1745–53. doi: 10.1017/S0033291709992236
57. Hay P. Current approach to eating disorders: a clinical update. Intern Med J
(2020) 50(1):24–9. doi: 10.1111/imj.14691
58. Lester NA, Keel PK, Lipson SF. Symptom fluctuation in bulimia nervosa:
Relation to menstrual-cycle phase and cortisol levels. Psychol Med (2003) 33(1):51–
60. doi: 10.1017/S0033291702006815
59. Klump KL, Racine SE, Hildebrandt B, Alexandra Burt S, Neale M, Sisk CL,
et al. Influences of ovarian hormones on dysregulated eating: A comparison of
associations in women with versus women without binge episodes. Clin Psychol Sci
(2014) 2(5):545–59. doi: 10.1177/2167702614521794
60. Klump KL, Keel PK, Racine SE, Burt AA, Neale M, Sisk CL, et al. The
interactive effects of estrogen and progesterone on changes in emotional eating
across the menstrual cycle. J Abnorm Psychol (2013) 122(1):131–7. doi: 10.1037/
a0029524
61. Zhu LL, Blair H, Cao J, Yuen T, Latif R, Guo L, et al. Blocking antibody to
the b-subunit of FSH prevents bone loss by inhibiting bone resorption and
stimulating bone synthesis. Proc Natl Acad Sci U S A (2012) 109(36):14574–9.
doi: 10.1073/pnas.1212806109
62. Trout KK, Basel-Brown L, Rickels MR, Schutta MH, Petrova M, Freeman
EW, et al. Insulin sensitivity, food intake, and cravings with premenstrual
syndrome: A pilot study. J Women’s Heal (2008) 17(4):657–65. doi: 10.1089/
jwh.2007.0594
63. Racine SE, Culbert KM, Keel PK, Sisk CL, Alexandra Burt S, Klump KL.
Differential associations between ovarian hormones and disordered eating
symptoms across the menstrual cycle in women. Int J Eat Disord (2012) 45
(3):333–44. doi: 10.1002/eat.20941
64. Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V. Insulin
resistance, secretion, and metabolism in users of oral contraceptives. JClin
Endocrinol Metab (1992) 74(1):64–70. doi: 10.1210/jcem.74.1.1530790
65. Diamanti-Kandarakis E, Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Nestler
JE. Controversies in endocrinology - a modern medical quandary: Polycystic ovary
syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab
(2003) 88(5):1927–32. doi: 10.1210/jc.2002-021528
66. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic
ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev
(2012) 33(6):981–1030. doi: 10.1210/er.2011-1034
67. Sutter-Dub MT, Kaaya A, latif SA, Sodoyez-Goffaux F, Sodoyez JC, Sutter
BCJ. Progesterone and synthetic steroids produce insulin resistance at the post-
receptor level in adipocytes of female rats. Steroids (1988) 52(5–6):583–608. doi:
10.1016/0039-128X(88)90125-0
68. Anderson RC, Newton CL, Anderson RA, Millar RP. Gonadotropins and
their analogs: Current and potential clinical applications. Endocr Rev (2018) 39
(6):911–37. doi: 10.1210/er.2018-00052
69. Zaidi M, New M, Blair H, Zalone A. Actions of pituitary hormones beyond
traditional targets. J Endocrinol (2018) 237(3):R83–98. doi: 10.1530/JOE-17-0680
70. Liu XM, Chan HC, Ding GL, Cai J, Song Y, Wang TT, et al. FSH regulates fat
accumulation and redistribution in aging through the Gai/Ca2+/CREB pathway.
Aging Cell (2015) 14(3):409–20. doi: 10.1111/acel.12331
71. Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro VE, Dhawan S, et al.
Blocking FSH induces thermogenic adipose tissue and reduces body fat. Obstet
Gynecol Surv (2017) 72(10):601–2. doi: 10.1097/01.ogx.0000525900.85600.c2
72. Quinn M, Xu X MR. Estrogen deficiency promotes hepatic steatosis via a
glucocorticoid receptor-dependent mechanism in mice. Cell Rep (2018) 22
(10):2690–701. doi: 10.1016/j.celrep.2018.02.041
73. Cui H, Zhao G, Liu R, Zheng M, Chen J, Wen J. FSH stimulates lipid
biosynthesis in chicken adipose tissue by upregulating the expression of its receptor
FSHR. J Lipid Res (2012) 53(5):909–17. doi: 10.1194/jlr.M025403
74. Han X, Guan Z, Xu M, Zhang Y, Yao H, Meng F, et al. A novel follicle-
stimulating hormone vaccine for controlling fat accumulation. Theriogenology
(2020) 148:103–11. doi: 10.1016/j.theriogenology.2020.03.005
75. Ellacott KLJ, Cone RD. The central melanocortin system and the integration
of short- and long-term regulators of energy homeostasis. Recent Prog Horm Res
(2004) 59:395–408. doi: 10.1210/rp.59.1.395
76. Yang YK, Harmon CM. Recent developments in our understanding of
melanocortin system in the regulation of food intake. Obes Rev (2003) 4(4):239–48.
doi: 10.1046/j.1467-789X.2003.00104.x
77. Rossi M, Kim MS, Morgan DGA, Small CJ, Edwards CMB, Sunter D, et al. A
c-terminal fragment of agouti-related protein increases feeding and antagonizes the
effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology (1998) 139
(10):4428–31. doi: 10.1210/endo.139.10.6332
78. De Souza FSJ, Nasif S, Lopez-Leal R, Levi DH, Low MJ, Rubinsten M. The
estrogen receptor acolocalizes with proopiomelanocortin in hypothalamic
neurons and binds to a conserved motif present in the neuron-specific enhancer
nPE2. Eur J Pharmacol (2011) 660(1):181–7. doi: 10.1016/j.ejphar.2010.10.114
79. Roepke TA. Oestrogen modulates hypothalamic control of energy
homeostasis through multiple mechanisms. J Neuroendocrinol (2009) 21(2):141–
50. doi: 10.1111/j.1365-2826.2008.01814.x
80. Richard CD, Tolle V, Low MJ. Meal pattern analysis in neural-specific
proopiomelanocortindeficient mice. Eur J Pharmacol (2011) 660(1):131–8. doi:
10.1016/j.ejphar.2010.12.022
81. Zemel MB, Shi H. Pro-opiomelanocortin (POMC) deficiency and peripheral
melanocortins in obesity. Nutr Rev (2000) 58(6):177–80. doi: 10.1111/j.1753-
4887.2000.tb01857.x
82. Roepke TA, Ronnekleiv OK, Kelly MJ. Physiological consequences of
membrane-initiated estrogen signaling in the brain. Front Biosci (2011) 16
(4):1560–73. doi: 10.2741/3805
83. Smith A, Rønnekleiv O, Kelly M. Gq-mER signaling has opposite effects on
hypothalamic orexigenic and anorexigenic neurons. Steroids (2014) 0, 31–5. doi:
10.1016/j.steroids.2013.11.007
84. Stincic TL, Grachev P, Bosch MA, Rønnekleiv OK, Kelly MJ. Estradiol
drives the anorexigenic activity of proopiomelanocortin neurons in female mice.
eNeuro (2018) 5(4):1–18. doi: 10.1523/ENEURO.0103-18.2018
85. Pillot B, Duraffourd C, Begeot M, Joly A, Luquet S, Houberdon I, et al. Role
of hypothalamic melanocortin system in adaptation of food intake to food protein
increase in mice. PloS One (2011) 6(4):e19107. doi: 10.1371/journal.pone.0019107
86. Olofsson LE, Pierce AA, Xu AW. Functional requirement of AgRP and NPY
neurons in ovarian cycle-dependent regulation of food intake. Proc Natl Acad Sci U
SA(2009) 106(37):15932–7. doi: 10.1073/pnas.0904747106
87. Santollo J, Yao D, Neal-Perry G, Etgen AM. Middle-aged female rats retain
sensitivity to the anorexigenic effect of exogenous estradiol. Behav Brain Res (2012)
232(1):159–64. doi: 10.1016/j.bbr.2012.04.010
88. Levin ER. Plasma membrane estrogen receptors. Trends Endocrinol Metab
(2009) 20(10):477–82. doi: 10.1016/j.tem.2009.06.009
89. Qiu LR, Germann J, Spring S, Alm C, Vousden DA, Palmert MR, et al.
Hippocampal volumes differ across the mouse estrous cycle, can change within
24hours, and associate with cognitive strategies. Neuroimage (2013) 83:593–8. doi:
10.1016/j.neuroimage.2013.06.074
90. Arevalo MA, Azcoitia I, Garcia-Segura LM. The neuroprotective actions of
oestradiol and oestrogen receptors. Nat Rev Neurosci (2015) 16(1):17–29. doi:
10.1038/nrn3856
91. Sharma G. G-Protein-Coupled estrogen receptor (GPER) and sex-specific
metabolic homeostasis. Adv Exp Med Biol (2017) 1043:427–53. doi: 10.1007/978-3-
319-70178-3_20
92. Qiu J, Bosch MA, Tobias SC, Krust A, Graham SM, Murphy SJ, et al. A G-
protein-coupled estrogen receptor is involved in hypothalamic control of energy
homeostasis. J Neurosci (2006) 26(21):5649–55. doi: 10.1523/JNEUROSCI.0327-
06.2006
93. Marraudino M, Carrillo B, Bonaldo B, Llorente R, Campioli E, Garate I, et al.
G Protein-coupled estrogen receptor immunoreactivity in the rat hypothalamus is
widely distributed in neurons, astrocytes, and oligodendrocytes, fluctuates during
the estrous cycle, and is sexually dimorphic. Neuroendocrinology (2021) 111
(7):660–77. doi: 10.1159/000509583
94. Chouchani ET, Kazak L, Spiegelman BM. New advances in adaptive
thermogenesis: UCP1 and beyond. Cell Metab (2019) 29(1):27–37. doi: 10.1016/
j.cmet.2018.11.002
95. Harms M, Seale P. Brown and beige fat: Development, function and
therapeutic potential. Nat Med (2013) 19(10):1252–63. doi: 10.1038/nm.3361
96. Perkins MN, Rothwell NJ, Stock MJ, Stone TW. Activation of brown
adipose tissue thermogenesis by the ventromedial hypothalamus. Nature (1981)
289(5796):401–2. doi: 10.1038/289401a0
97. Yoshimatsu H, Egawa M, Bray GA. Sympathetic nerve activity after discrete
hypothalamic injections of l-glutamate. Brain Res (1993) 601(1–2):121–8. doi:
10.1016/0006-8993(93)91702-T
98. Lopez M, Varela L, Vazquez MJ, Rodrı
guez-Cuenca S. Hypothalamic
AMPK and fatty acid metabolism mediate thyroid regulation of energy balance.
Nat Med (2010) 16(9):1001–8. doi: 10.1038/nm.2207
99. Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vazquez MJ, et al.
BMP8B increases brown adipose tissue thermogenesis through both central and
peripheral actions. Cell (2012) 149(4):871–85. doi: 10.1016/j.cell.2012.02.066
100. Seoane-Collazo P, Martı
nezDeMorentinPB,FernøJ,Die
guez C,
Nogueiras R, Lopez M. Nicotine improves obesity and hepatic steatosis and ER
stress in diet-induced obese male rats. Endocrinology (2014) 155(5):1679–89. doi:
10.1210/en.2013-1839
101. Martı
nezDeMorentinPB,Gonza
lez-Garcı
a I, Martins L, Lage R,
Fernandez-Mallo D, Martı
nez-Sanchez N, et al. Estradiol regulates brown
Vigil et al. 10.3389/fendo.2022.951186
Frontiers in Endocrinology frontiersin.org12
adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab (2014) 20
(1):41–53. doi: 10.1016/j.cmet.2014.03.031
102. Lopez M, Nogueiras R, Tena-Sempere M, Dieguez C. Hypothalamic
AMPK: A canonical regulator of whole-body energy balance. Nat Rev Endocrinol
(2016) 12(7):421–32. doi: 10.1038/nrendo.2016.67
103.LiuH,XuY,HuF.AMPKintheventromedialnucleusofthe
hypothalamus: A key regulator for thermogenesis. Front Endocrinol (Lausanne)
(2020) 11:1–13. doi: 10.3389/fendo.2020.578830
104. Hardie DG, Ross FA, Hawley SA. AMPK: A nutrient and energy sensor
that maintains energy homeostasis. Nat Rev Mol Cell Biol (2012) 13(4):251–62.
doi: 10.1038/nrm3311
105. Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown
adipose tissue thermogenesis and energy expenditure. Cell Metab (2014) 19
(5):741–56. doi: 10.1016/j.cmet.2014.02.007
106. Minokoshi Y, Alquier T, Furukawa H, Kim YB, Lee A, Xue B, et al. AMP-
kinase regulates food intake by responding to hormonal and nutrient signals in the
hypothalamus. Nature (2004) 428(6982):569–74. doi: 10.1038/nature02440
107. Lopez M, Lage R, Saha AK, Perez-Tilve D, Vazquez MJ, Varela L, et al.
Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell
Metab (2008) 7(5):389–99. doi: 10.1016/j.cmet.2008.03.006
108. Liu J, Conde K, Zhang P, Lilascharoen V. Enhanced AMPA receptor
trafficking mediates the anorexigenic effect of endogenous glucagon like peptide-1
in the paraventricular hypothalamus. Neuron (2017) 96(4):897–909. doi: 10.1016/
j.neuron.2017.09.042
109. Hardie DG. Targeting an energy sensor to treat diabetes. Sci (80- ). (2017)
357(6350):455–6. doi: 10.1126/science.aao1913
110. Stark R, Ashley SE, Andrews ZB. AMPK and the neuroendocrine
regulation of appetite and energy expenditure. Mol Cell Endocrinol (2013) 366
(2):215–23. doi: 10.1016/j.mce.2012.06.012
111. Lin SC, Hardie DG. AMPK: Sensing glucose as well as cellular energy
status. Cell Metab (2018) 27(2):299–313. doi: 10.1016/j.cmet.2017.10.009
112. Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological
significance. Physiol Rev (2004) 84(1):277–359. doi: 10.1152/physrev.00015.2003
113. Yoshida T, Nishioka H, Yoshioka K, Kondo M. Reduced norepinephrine
turnover in interscapular brown adipose tissue of obese rats after ovariectomy.
Metabolism (1987) 36(1):1–6. doi: 10.1016/0026-0495(87)90054-0
114. Rodrı
guez AM, Monjo M, Roca P, Palou A. Opposite actions of
testosterone and progesterone on UCP1 mRNA expression in cultured brown
adipocytes. Cell Mol Life Sci (2002) 59(10):1714–23. doi: 10.1007/PL00012499
115. Monjo M, Rodrı
guez AM, Palou A, Roca P. Direct effects of testosterone,
17b-estradiol, and progesterone on adrenergic regulation in cultured brown
adipocytes: Potential mechanism for gender-dependent thermogenesis.
Endocrinology (2003) 144(11):4923–30. doi: 10.1210/en.2003-0537
116. Rodriguez-Cuenca S, Monjo M, Frontera M, Gianotti M, Proenza AM,
Roca P. Sex steroid receptor expression profile in brown adipose tissue. Effects
Hormonal Status Cell Physiol Biochem (2007) 20(6):877–86. doi: 10.1159/
000110448
117. Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, et al.
Occurrence of brown adipocytes in