[Show abstract][Hide abstract] ABSTRACT: Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs.
Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection.
Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus.
The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.
[Show abstract][Hide abstract] ABSTRACT: Survival of free-living animals depends on the ability to maintain core body temperature in the face of rapid and dramatic changes in their thermal environment. If food intake is not adjusted to meet the changing energy demands associated with changes of ambient temperature, a serious challenge to body energy stores can occur. To more fully understand the coupling of thermoregulation to energy homeostasis in normal animals and to investigate the role of the adipose hormone leptin to this process, comprehensive measures of energy homeostasis and core temperature were obtained in leptin-deficient ob/ob mice and their wild-type (WT) littermate controls when housed under cool (14°C), usual (22°C) or ∼ thermoneutral (30°C) conditions. Our findings extend previous evidence that WT mice robustly defend normothermia in response to either a lowering (14°C) or an increase (30°C) of ambient temperature without changes in body weight or body composition. In contrast, leptin-deficient, ob/ob mice fail to defend normothermia at ambient temperatures lower than thermoneutrality and exhibit marked losses of both body fat and lean mass when exposed to cooler environments (14°C). Our findings further demonstrate a strong inverse relationship between ambient temperature and energy expenditure in WT mice, a relationship that is preserved in ob/ob mice. However, thermal conductance analysis indicates defective heat retention in ob/ob mice, irrespective of temperature. While a negative relationship between ambient temperature and energy intake also exists in WT mice, this relationship is disrupted in ob/ob mice. Thus, to meet the thermoregulatory demands of different ambient temperatures, leptin signaling is required for adaptive changes in both energy intake and thermal conductance. A better understanding of the mechanisms coupling thermoregulation to energy homeostasis may lead to the development of new approaches for the treatment of obesity.
PLoS ONE 03/2015; 10(3):e0119391. DOI:10.1371/journal.pone.0119391 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the antidiabetic effects of leptin require intact neuronal melanocortin signaling in rodents with uncontrolled diabetes (uDM), increased melanocortin signaling is not sufficient to mimic leptin's glucose-lowering effects. The current studies were undertaken to clarify the role of melanocortin signaling in leptin's ability to correct metabolic and neuroendocrine disturbances associated with uDM. To accomplish this, bilateral cannulae were implanted in the lateral ventricle of rats with streptozotocin-induced diabetes, and leptin was coinfused with varying doses of the melanocortin 3/4 receptor (MC3/4R) antagonist, SHU9119. An additional cohort of streptozotocin-induced diabetes rats received intracerebroventricular administration of either the MC3/4R agonist, melanotan-II, or its vehicle. Consistent with previous findings, leptin's glucose-lowering effects were blocked by intracerebroventricular SHU9119. In contrast, leptin-mediated suppression of hyperglucagonemia involves both melanocortin dependent and independent mechanisms, and the degree of glucagon inhibition was a associated with reduced plasma ketone body levels. Increased CNS melanocortin signaling alone fails to mimic leptin's ability to correct any of the metabolic or neuroendocrine disturbances associated with uDM. Moreover, the inability of increased melanocortin signaling to lower diabetic hyperglycemia does not appear to be secondary to release of the endogenous MC3/4R inverse agonist, Agouti-related peptide (AgRP), because AgRP knockout mice did not show increased susceptibility to the antidiabetic effects of increased MC3/4R signaling. Overall, these data suggest that 1) AgRP is not a major driver of diabetic hyperglycemia, 2) mechanisms independent of melanocortin signaling contribute to leptin's antidiabetic effects, and 3) melanocortin receptor blockade dissociates leptin's glucose-lowering effect from its action on other features of uDM, including reversal of hyperglucagonemia and ketosis, suggesting that brain control of ketosis, but not blood glucose levels, is glucagon dependent.
[Show abstract][Hide abstract] ABSTRACT: Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance, and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition, and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases.
[Show abstract][Hide abstract] ABSTRACT: Oxytocin (OT)-elicited hypophagia has been linked to neural activity in the nucleus of the solitary tract (NTS). Because plasma OT levels increase following a meal, we hypothesized that circulating OT acts at both peripheral and hindbrain OT receptors (OTRs) to limit food intake. To initially determine whether circulating OT inhibits food intake by acting at hindbrain OTRs, we pre-treated rats with an OTR antagonist administered into the fourth ventricle (4V) followed by either central or systemic OT administration. Administration of the OTR antagonist into the 4V blocked anorexia induced by either 4V or intraperitoneal (i.p.) injection of OT. However, blockade of peripheral OTRs also weakened the anorectic response to i.p. OT. Our data suggest a predominant role for hindbrain OTRs in the hypophagic response to peripheral OT administration. To elucidate central mechanisms of OT hypophagia, we tested whether OT activates NTS catecholaminergic neurons. OT (i.p.) increased the number of NTS cells expressing c-Fos, of which 10-15% were catecholaminergic. Further, electrophysiological studies in mice revealed that OT stimulated 47% (8/17) of NTS catecholamine neurons through a pre-synaptic mechanism. However, OT-elicited hypophagia did not appear to require activation of alpha1 (α1)-adrenoceptors, and blockade of glucagon-like peptide-1 receptors similarly did not attenuate anorexia induced by OT. These findings demonstrate that 1) OT elicits satiety through both central and peripheral OTRs and 2) although catecholamine neurons are a downstream target of OT signaling in the NTS, the hypophagic effect is mediated independently of α1-adrenoceptor signaling.
[Show abstract][Hide abstract] ABSTRACT: Under normal conditions, food intake and energy expenditure are balanced by a homeostatic system that maintains stability of body fat content over time. However, this homeostatic system can be overridden by the activation of 'emergency response circuits' that mediate feeding responses to emergent or stressful stimuli. Inhibition of these circuits is therefore permissive for normal energy homeostasis to occur, and their chronic activation can cause profound, even life-threatening, changes in body fat mass. This Review highlights how the interplay between homeostatic and emergency feeding circuits influences the biologically defended level of body weight under physiological and pathophysiological conditions.
[Show abstract][Hide abstract] ABSTRACT: Context.Fibroblast growth factor 19 (FGF19) improves glycemic control in diabetic animals and is secreted from the gastrointestinal tract following meals in response to bile acid stimulation.Objective.We sought to understand how ingestion of carbohydrates, protein or lipids affect both FGF19 and bile acid concentrations in human plasma, with the hypothesis that variation in the bile acid response to different macronutrients would predict differences in plasma FGF19 levels.Design.This was a randomized, within-subjects crossover study.Setting.The study was conducted at a University Clinical Research Center.Participants.There were 16 healthy human subjects included in the study.Interventions.Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided to each participant on three separate occasions.Main Outcome Measures.The magnitudes of postprandial rises of plasma FGF19 and total bile acid levels were determined.Results.All beverages induced an initial transient decline of plasma FGF19 levels during the first 60 min following consumption. For FGF19, the ingestion of carbohydrate was associated with the fastest and highest increase of plasma levels, returning to baseline at 5h. By comparison, the protein beverage induced a modest but significant elevation of FGF19 levels that peaked at the end of the 6-h sampling interval, while a lipid beverage was without effect. In contrast, total bile acid levels increased in plasma only in response to a high lipid beverage, demonstrating a marked divergence between the FGF19 and bile acid response to lipid vs. carbohydrate.Conclusions.A bile acid-independent mechanism is implicated in the effect of meals to raise plasma FGF19 concentrations.
The Journal of Clinical Endocrinology and Metabolism 12/2013; 99(2). DOI:10.1210/jc.2013-3129 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as 'glucose effectiveness', account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.
[Show abstract][Hide abstract] ABSTRACT: Leptin, a hormone secreted by adipocytes, plays a crucial role in regulating energy balance. Estrogen, like leptin, reduces food intake and adiposity while increasing energy expenditure in animals and humans of both sexes through its actions on the central nervous system. We reviewed the literature for studies of the effects of exogenously administered estrogen on serum leptin concentrations and adiposity in women.
Using PubMed/Medline, we searched for studies of hormone therapy that enrolled healthy postmenopausal women. Studies were further evaluated to determine if leptin and adiposity were monitored both at baseline and throughout a treatment period of at least 2 months.
Twenty articles met inclusion criteria. We found no consistent effects of exogenous estrogen on serum leptin concentrations, adiposity, or weight gain.
Despite suggestive data from animal studies, the current literature does not provide compelling evidence that estrogen therapy attenuates weight gain, alters circulating leptin levels, or improves leptin action in postmenopausal women.
Menopause (New York, N.Y.) 10/2013; 21(4). DOI:10.1097/GME.0000000000000117 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal.
The Journal of clinical investigation 10/2013; 123(11). DOI:10.1172/JCI70710 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The β-defensins are a class of small, cationic proteins first recognized as antimicrobial components of the innate and adaptive immune system. More recently, one of the major β-defensins produced in skin, β-defensin 3, has been discovered to function as a melanocortin receptor ligand in vivo and in vitro, but its biophysical and pharmacological basis of action has been enigmatic. Here, we report functional and biochemical studies focused on human β-defensin 3 (HBD3) and melanocortin receptors 1 and 4. Genetic and pharmacologic studies indicate that HBD3 acts as a neutral melanocortin receptor antagonist capable of blocking the action of either stimulatory agonists such as α-melanocyte stimulating hormone or inhibitory inverse agonists such as Agouti signaling protein (ASIP) and Agouti-related protein (AGRP). A comprehensive structure-function analysis demonstrates that two patches of positively charged residues, located on opposite poles of HBD3 and spatially organized by the compact β-defensin fold, are primarily responsible for high-affinity binding to melanocortin receptors. These findings identify a distinct mode of melanocortin receptor-ligand interactions based primarily on electrostatic complementarity, with implications for designing ligands that target melanocortin and potentially other seven transmembrane receptors.
[Show abstract][Hide abstract] ABSTRACT: In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's anti-diabetic effects since leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus (STZ-DM). This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production (HGP) and plasma glucagon levels, but had no effect on tissue glucose uptake in skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine if VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 (SF1) neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's anti-diabetic action, but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.
[Show abstract][Hide abstract] ABSTRACT: The mediobasal hypothalamus (MBH) plays a central role in the regulation of food intake and energy balance. Although the excitatory neurotransmitter glutamate is implicated in energy balance regulation by the MBH, the hypothesis that feeding elicits local glutamate release remains untested. To test this hypothesis, we employed a glutamate biosensor that measures glutamate concentrations at 1-s intervals in conscious, freely behaving rats. Results indicate that feeding is associated with an increase of MBH glutamate concentration that occurs within 1-2 s of oral contact with a food pellet, and the glutamate response to a palatable high-fat pellet is greatly exaggerated relative to chow. In contrast, glutamate responses were not observed during water ingestion or other observed behaviors. These findings indicate that feeding is associated with rapid release of glutamate in the MBH, that this release is exaggerated with an obesogenic food, and that this response is likely stimulated by orosensory factors.
[Show abstract][Hide abstract] ABSTRACT: Recent advances in human brown adipose tissue (BAT) imaging technology have renewed interest in the identification of BAT activators for the treatment of obesity and diabetes. In uncontrolled diabetes (uDM), activation of BAT is implicated in glucose lowering mediated by intracerebroventricular (icv) administration of leptin, which normalizes blood glucose levels in streptozotocin (STZ)-induced diabetic rats. The potent effect of icv leptin to increase BAT glucose uptake in STZ-diabetes is accompanied by the return of reduced plasma thyroxine (T4) levels and BAT uncoupling protein-1 (Ucp1) mRNA levels to non-diabetic controls. We therefore sought to determine whether activation of thyroid hormone receptors is sufficient in and of itself to lower blood glucose levels in STZ-diabetes, and whether this effect involves activation of BAT. We found that although systemic administration of the thyroid hormone (TR)-β selective agonist GC-1 increases energy expenditure and induces further weight loss in STZ-diabetic rats, it neither increased BAT glucose uptake nor attenuated diabetic hyperglycemia. Even when GC-1 was administered in combination with a β3-AR agonist to mimic sympathetic nervous system activation, glucose uptake was not increased in STZ-diabetic rats nor was blood glucose lowered, yet this intervention potently activated BAT. Similar results were observed in animals treated with active thyroid hormone (T3) instead of GC-1. Taken together, our data suggest that neither returning normal plasma thyroid hormone levels nor BAT activation have any impact on diabetic hyperglycemia, and that in BAT, increases of Ucp1 gene expression and glucose uptake are readily dissociated from one another in this setting.
[Show abstract][Hide abstract] ABSTRACT: Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes, and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.
[Show abstract][Hide abstract] ABSTRACT: Diabetes is a major worldwide problem. Despite some progress in the development of new antidiabetic agents, the ability to maintain tight glycemic control in order to prevent renal, retinal, and neuropathic complications of diabetes without adverse complications still remains a challenge. Recent evidence suggests, however, that in addition to playing a key role in the regulation of energy homeostasis, the adiposity hormone leptin also plays an important role in the control of glucose metabolism via its actions in the brain. This review examines the role of leptin action in the central nervous system and the mechanisms whereby leptin mediates its effects to regulate glucose metabolism. These findings suggest that defects or dysfunction in leptin signaling may contribute to the etiology of diabetes and raise the possibility that either leptin or downstream targets of leptin may have therapeutic potential for the treatment of diabetes.
[Show abstract][Hide abstract] ABSTRACT: Despite the suggestion that reduced energy expenditure may be a key contributor to the obesity pandemic, few studies have tested whether acutely reduced energy expenditure is associated with a compensatory reduction in food intake. The homeostatic mechanisms that control food intake and energy expenditure remain controversial and are thought to act over days to weeks. We evaluated food intake in mice using two models of acutely decreased energy expenditure: 1) increasing ambient temperature to thermoneutrality in mice acclimated to standard laboratory temperature or 2) exercise cessation in mice accustomed to wheel running. Increasing ambient temperature (from 21 °C to 28 °C) rapidly decreased energy expenditure, demonstrating that thermoregulatory energy expenditure contributes to both light cycle (40 ± 1%) and dark cycle energy expenditure (15 ± 3%) at normal ambient temperature (21 °C). Reducing thermoregulatory energy expenditure acutely decreased food intake primarily during the light cycle (65 ± 7%), thus conflicting with the delayed compensation model, but did not alter spontaneous activity. Acute exercise cessation decreased energy expenditure only during the dark cycle (14 ± 2% at 21 °C; 21 ± 4% at 28 °C), while food intake was reduced during the dark cycle (0.9 ± 0.1 g) in mice housed at 28 °C, but during the light cycle (0.3 ± 0.1 g) in mice housed at 21 °C. Cumulatively, there was a strong correlation between the change in daily energy expenditure and the change in daily food intake (R(2) = 0.51, p<0.01). We conclude that acutely decreased energy expenditure decreases food intake suggesting that energy intake is regulated by metabolic signals that respond rapidly and accurately to reduced energy expenditure.
PLoS ONE 08/2012; 7(8):e41473. DOI:10.1371/journal.pone.0041473 · 3.23 Impact Factor