FGF21 mediating sex dependent response to dietary macronutrients.

Sex is key variable influencing body composition and substrate utilization. At rest, females maintain greater adiposity than males and resist the mobilization of fat. Males maintain greater lean muscle mass and mobilize fat readily. Determining the mechanisms that direct these sex-dependent effects is important for both reproductive and metabolic health. Here we highlight the fundamental importance of sex in shaping metabolic physiology and assess growing evidence that the hepatokine Fibroblast growth factor-21 (FGF21) plays a mechanistic role to facilitate sex-dependent responses to a changing nutritional environment. First, we examine the importance of sex in modulating body composition and substrate utilization. We summarize new data that point towards sex-biased effects of pharmacologic FGF21 administration on these endpoints. When energy is not limited, metabolic responses to FGF21 mirror broader sex differences; FGF21-treated males conserve lean mass at the expense of increased lipid catabolism whereas FGF21-treated females conserve fat mass at the expense of reduced lean mass. Next, we examine the importance of sex in modulating the endogenous secretion of FGF21 in response to changing macronutrient and energy availability. During the resting state when energy is not limited, macronutrient imbalance increases the secretion of FGF21 more so in males than females. When energy is limited, the effect of sex on both the secretion of FGF21 and its metabolic actions may be reversed. Altogether, we argue that a growing literature supports FGF21 as a plausible mechanism contributing to the sex dependent mobilization vs preservation of lipid storage and highlight the need for further research.

Context matters for addressing controversies in FGF21 biology.

Recent discoveries by Solon-Biet and colleagues highlight the importance of nutritional context for addressing current controversies in Fibroblast Growth Factor 21 (FGF21) biology. Through a series of complex studies, the authors explored the physiological and pharmacological effects of FGF21 on feeding behavior and energy balance under differing nutritional and metabolic statuses.

FGF21 Induces Skeletal Muscle Atrophy and Increases Amino Acids in Female Mice: A Potential Role for Glucocorticoids.

Fibroblast growth factor-21 (FGF21) is an intercellular signaling molecule secreted by metabolic organs, including skeletal muscle, in response to intracellular stress. FGF21 crosses the blood-brain barrier and acts via the nervous system to coordinate aspects of the adaptive starvation response, including increased lipolysis, gluconeogenesis, fatty acid oxidation, and activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Given its beneficial effects for hepatic lipid metabolism, pharmaceutical FGF21 analogues are used in clinical trials treatment of fatty liver disease. We predicted pharmacologic treatment with FGF21 increases HPA axis activity and skeletal muscle glucocorticoid signaling and induces skeletal muscle atrophy in mice. Here we found a short course of systemic FGF21 treatment decreased muscle protein synthesis and reduced tibialis anterior weight; this was driven primarily by its effect in female mice. Similarly, intracerebroventricular FGF21 reduced tibialis anterior muscle fiber cross-sectional area; this was more apparent among female mice than male littermates. In agreement with the reduced muscle mass, the topmost enriched metabolic pathways in plasma collected from FGF21-treated females were related to amino acid metabolism, and the relative abundance of plasma proteinogenic amino acids was increased up to 3-fold. FGF21 treatment increased hypothalamic Crh mRNA, plasma corticosterone, and adrenal weight, and increased expression of glucocorticoid receptor target genes known to reduce muscle protein synthesis and/or promote degradation. Given the proposed use of FGF21 analogues for the treatment of metabolic disease, the study is both physiologically relevant and may have important clinical implications.

Dietary protein restriction modulates 'dessert' intake after a meal, via fibroblast growth factor 21 (FGF21).

Pharmacological administration of fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load diet could reduce the consumption of sweet desserts in sated mice. Here, we tested the prediction that individuals maintained on a low P: E diet, and offered a highly palatable sweet 'dessert' following a pre-load meal, would eat less of the sugary snack compared to controls-due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals maintained on the low P: E diet, and offered a very high-protein pellet as 'dessert' or snack after a meal, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21ΔL) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21ΔL mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load diet is not sufficient to reduce the consumption of sweet desserts, though it effectively increases the subsequent intake of dietary protein in male mice.

The macronutrient content of a meal modulates subsequent 'dessert' intake, via Fibroblast Growth Factor 21 (FGF21).

Pharmacological administration of Fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load meal could reduce the later consumption of sweet desserts. Here, we tested the prediction that individuals eating a low P: E pre-load meal, and next offered a highly palatable sweet 'dessert', would eat less of the sugary snack compared to controls, due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals eating a low protein pre-load meal, and subsequently offered a very high-protein pellet as 'dessert' or snack, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21 ΔL ) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21 ΔL mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load is not sufficient to reduce later consumption of sweet dessert, though it effectively increases the subsequent intake of dietary protein in male mice.

Fibroblast growth factor 21 and dietary macronutrient intake in female mice.

Fibroblast growth factor- 21 (FGF21) is a metabolic stress hormone that is released from the liver in response to various nutritional challenges. Because of its notable effects to improve metabolic health, including body fat loss, glucose control, and hepatosteatosis, several pharmaceutical analogs of FGF21 are in development for the treatment of metabolic disease. In addition, a small but developing literature clearly demonstrates that FGF21 also controls feeding behavior. Pharmacological administration of FGF21 reduces the consumption of simple sugars and other sweet tastants, and it increases the consumption of dietary proteins in males, suggesting another potential mechanism by which FGF21-treatment could improve metabolic health- by promoting healthy eating. Despite that sex is a key biological variable influencing feeding behavior and macronutrient selection, the current literature to date primarily on males. In this study, we investigated the effect of FGF21 on sucrose intake and macronutrient selection in female mice. Similar to our previous findings in male mice, we report that FGF21 administration decreases the consumption of sucrose solution by females, and that this is offset by increased chow intake. Also in agreement with our previous findings in males, we report that FGF21 increases the consumption of dietary protein by female mice, and this is offset by either reduced carbohydrate or by reduced fat intake. Lastly, we find that the effect of FGF21 to direct macronutrient intake in females depends on its actions in neurons. Overall, our data support a role for FGF21 to direct macronutrient intake in a similar manner in female and male mice.

FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk.

The liver regulates energy partitioning and use in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor 21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate use to reduce hepatic lipid storage. Here we report that FGF21 altered hepatic transcriptional and metabolic responses, and reduced liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor → cAMP → exchange protein directly activated by cAMP signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.

Adipose Mitochondrial Complex I Deficiency Modulates Inflammation and Glucose Homeostasis in a Sex-Dependent Manner.

Mitochondrial dysfunction in adipose tissue has been associated with type 2 diabetes, but it is unclear whether it is a cause or the consequence. Mitochondrial complex I is a major site of reactive oxygen species generation and a therapeutic target. Here we report that genetic deletion of the complex I subunit Ndufs4 specifically in adipose tissue results in an increased propensity to develop diet-induced weight gain, glucose intolerance, and elevated levels of fat inflammatory genes. This outcome is apparent in young males but not in young females, suggesting that females are relatively protected from the adverse consequences of adipose mitochondrial dysfunction for metabolic health. Mutant mice of both sexes exhibit defects in brown adipose tissue thermogenesis. Fibroblast growth factor 21 (FGF21) signaling in adipose tissue is selectively blunted in male mutant mice relative to wild-type littermates, consistent with sex-dependent regulation of its autocrine/paracrine action in adipocytes. Together, these findings support that adipocyte-specific mitochondrial dysfunction is sufficient to induce tissue inflammation and can cause systemic glucose abnormalities in male mice.

Fibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior.

Fibroblast growth factor 21 (FGF21) is a stress hormone that is released from the liver in response to nutritional and metabolic challenges. In addition to its well-described effects on systemic metabolism, a growing body of literature now supports the notion that FGF21 also acts via the central nervous system to control feeding behavior. Here we review the current understanding of FGF21 as a hormone regulating feeding behavior in rodents, non-human primates, and humans. First, we examine the nutritional contexts that induce FGF21 secretion. Initial reports describing FGF21 as a 'starvation hormone' have now been further refined. FGF21 is now better understood as an endocrine mediator of the intracellular stress response to various nutritional manipulations, including excess sugars and alcohol, caloric deficits, a ketogenic diet, and amino acid restriction. We discuss FGF21's effects on energy intake and macronutrient choice, together with our current understanding of the underlying neural mechanisms. We argue that the behavioral effects of FGF21 function primarily to maintain systemic macronutrient homeostasis, and in particular to maintain an adequate supply of protein and amino acids for use by the cells.

Assessment of the role of FGF15 in mediating the metabolic outcomes of murine Vertical Sleeve Gastrectomy (VSG).

Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its co-morbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in human and its murine orthologue Fgf15 plays a pivotal role in this bile acid driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15 deficient mice. 6-8 weeks old male wildtype mice (WT) and Fgf15 deficient mice (KO) were fed a high fat diet (HFD) for 8 weeks. At 8th week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Post-surgery, mice were observed for 8 weeks while fed a HFD and then euthanized to collect tissues for experimental analysis. Fgf15 deficient (KO) mice lost weight post VSG, but glucose tolerance in KO mice did not improve post VSG compared to WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post VSG both WT and KO mice had similarly altered bile acid enterohepatic flux, however Fgf15 deficient mice post VSG had increased hepatic accumulation of free and esterified cholesterol leading to lipotoxicity related ER stress, inflammasome activation, and increased Fgf21 expression. Intact Fgf15 mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared to their canonical downstream signaling pathways.

Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease.

The melanocortin-4 receptor (MC4R) facilitates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress in male rodents and is a well known to regulator of energy balance. Mutations in the MC4R is the most common monogenic cause of obesity in humans and has been associated with sex-specific effects, but whether stress regulation by the MC4R is sex-dependent, and whether the MC4R facilitates HPA responses to chronic stress, is unknown. We hypothesized that MC4R-signaling contributes to HPA axis dysregulation and metabolic pathophysiology following chronic stress exposure. We measured changes in energy balance, HPA axis tone, and vascular remodeling during chronic variable stress (CVS) in male and female rats with MC4R loss-of-function. Rats were placed into three groups (n = 9-18/genotype/sex) and half of each group was subjected to CVS for 30 days or were non-stressed littermate controls. All rats underwent an acute restraint stress challenge on Day 30. Rats were euthanized on Day 31, adrenals collected for weight, and descending aortas fixed for morphological indices of vascular pathophysiology. We observed a marked interaction between Mc4r genotype and sex for basal HPA axis tone and acute stress responsivity. MC4R loss-of-function blunted both endpoints in males but exaggerated them in females. Contrary to our hypothesis, Mc4r genotype had no effect on either HPA axis responses or metabolic responses to chronic stress. Heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females. Lay summary The hypothalamic melanocortin system is an important regulator of energy balance and stress responses. Here, we report a sex-difference in the stress reactivity of rats with a mutation in this system. Our findings highlight how stress may regulate metabolism differently in males and females and may provide insight into sex-differences associated with this mutation in humans.

Fibroblast Growth Factor-21 Controls Dietary Protein Intake in Male Mice.

Whereas carbohydrates and lipids are stored as glycogen and fat, there is no analogous inert storage form of protein. Therefore, continuous adjustments in feeding behavior are needed to match amino acid supply to ongoing physiologic need. Neuroendocrine mechanisms facilitating this behavioral control of protein and amino acid homeostasis remain unclear. The hepatokine fibroblast growth factor-21 (FGF21) is well positioned for such a role, as it is robustly secreted in response to protein and/or amino acid deficit. In this study, we tested the hypothesis that FGF21 feeds back at its receptors in the nervous system to shift macronutrient selection toward protein. In a series of behavioral tests, we isolated the effect of FGF21 to influence consumption of protein, fat, and carbohydrate in male mice. First, we used a three-choice pure macronutrient-diet paradigm. In response to FGF21, mice increased consumption of protein while reducing carbohydrate intake, with no effect on fat intake. Next, to determine whether protein or carbohydrate was the primary-regulated nutrient, we used a sequence of two-choice experiments to isolate the effect of FGF21 on preference for each macronutrient. Sweetness was well controlled by holding sucrose constant across the diets. Under these conditions, FGF21 increased protein intake, and this was offset by reducing the consumption of either carbohydrate or fat. When protein was held constant, FGF21 had no effect on macronutrient intake. Lastly, the effect of FGF21 to increase protein intake required the presence of its co-receptor, ß-klotho, in neurons. Taken together, these findings point to a novel liver→nervous system pathway underlying the regulation of dietary protein intake via FGF21.

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21.

In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual's nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect.

Sex Differences in the Hormonal and Metabolic Response to Dietary Protein Dilution.

Consumption of a low-protein, high-carbohydrate diet induces a striking increase in circulating fibroblast growth factor-21 (FGF21), which is associated with improved cardiometabolic health and increased longevity. Increased lifespan during this dietary protein "dilution" has been explained by resource-mediated trade-offs between reproduction and survival, such that fecundity is optimized at a greater relative intake of proteins/carbohydrates. The magnitude of this trade-off is thought to be sex-dependent. In this study, we tested the hypothesis that metabolic responses to dietary protein dilution are likewise dependent on sex. We maintained age-matched adult male and female C57BL/6J mice on isocaloric diets containing 22% fat and differing in the ratio of protein/carbohydrate. The normal protein (NP) control diet contained 18% protein and 60% carbohydrate by kcal. The protein diluted (PD) diet contained 4% protein and 74% carbohydrate. Consistent with previous reports, PD males gained less weight and less fat than did normal protein controls and exhibited both improved glucose tolerance and decreased plasma lipids. In contrast, these metabolic benefits were absent among age-matched females maintained on the same diets. Likewise, whereas circulating FGF21 was increased up to 66-fold among PD male mice, this was substantially blunted among female counterparts. Sex differences in energy balance, glucose control, and plasma FGF21 were reversed upon ovariectomy. Collectively, our findings support that female mice are relatively less sensitive to the metabolic improvements observed following dietary protein dilution. This is accompanied by blunted circulating levels of FGF21 and requires an intact female reproductive system.

Chronic stress and Rosiglitazone increase indices of vascular stiffness in male rats.

Prolonged and/or frequent exposure to psychological stress responses may lead to deterioration of organs and tissues, predisposing to disease. In agreement with this, chronic psychosocial stress is linked to greater cardiovascular risk, including increased incidence of atherosclerosis, myocardial ischemia, coronary heart disease, and death. Thus the association between stress and cardiovascular dysfunction represents an important node for therapeutic intervention in cardiovascular disease. Here we report that 2weeks of chronic variable stress (CVS) increased indices of vascular stiffness, including increased collagen deposition in the aortic adventitia and increased resting pulse pressure, in male rats. Thus CVS may represent a useful rodent model for stress-associated CVD, especially for aging populations for which widening pulse pressure is a well-known risk factor. Additionally, we report that the thiazolidinedione Rosiglitazone (RSG) blunts chronic stress-associated increases in circulating corticosterone. Despite this, RSG was not protective against adverse cardiovascular outcomes associated with chronic stress. Rather RSG itself is associated with increased pulse pressure, and this is exacerbated by chronic stress-highlighting that chronic stress may represent an additional contributor to RSG-associated cardiovascular risk.

Bile Acid Signaling: Mechanism for Bariatric Surgery, Cure for NASH?

Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease--nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precursor to the development of liver cirrhosis that may necessitate liver transplantation in the long run. Simultaneously, we and others have observed increased serum bile acids in humans and animals that undergo bariatric surgery. Specifically, our preclinical studies have included experimental procedures such as 'ileal transposition' or bile diversion and established procedures such as Roux-en-Y gastric bypass and the adjustable gastric band. Importantly, these effects are not simply the result of weight loss since our data show that the resolution of NASH and increase in serum bile acids are not seen in rodents that lose an equivalent amount of weight via food restriction. In particular, we have studied the role of altered bile acid signaling, in the potent impact of a bariatric procedure termed 'vertical sleeve gastrectomy' (VSG). In this review we focus on the mechanisms of NASH resolution and weight loss after VSG surgery. We highlight the fact that bariatric surgeries can be used as 'laboratories' to dissect the mechanisms by which these procedures work to improve obesity and fatty liver disease. We describe key bile acid signaling elements that may provide potential therapeutic targets for 'bariatric-mimetic technologies' that could produce benefits similar to bariatric surgery--but without the surgery!

Metabolic consequences of chronic intermittent mild stress exposure.

Chronic stress in humans has divergent effects on food intake, with some individuals reporting increased vs. decreased food intake during stress. This divergence may depend in part on stress intensity, with higher-intensity stressors preferentially promoting anorexia. Consistent with this idea, rodents given a high-intensity chronic variable stress paradigm have robustly decreased food intake and body weight gain. However, the metabolic effects of a less intense chronic stress paradigm are not clear. Thus in the present study, adult male rats were given chronic intermittent mild stress (CIMS) exposure (3 cycles, in which each cycle consists of once daily mild stress for 5 days/week for 2 weeks, followed by 2 weeks of no stress) vs. non-stress controls, combined with ongoing access to a palatable diet (PD; choice of chow, high-fat diet, 30% sucrose drink, and water) vs. control diet (chow and water). As expected, access to PD increased caloric intake, body weight gain, and adiposity, and impaired glucose tolerance. CIMS decreased body weight gain only during the first cycle of stress and did not affect body weight gain thereafter, regardless of diet. Moreover, CIMS did not alter total food intake, adiposity or glucose tolerance regardless of diet. Lastly, CIMS transiently increased high-fat diet preference in PD-fed rats during the first stress cycle. Collectively, these results suggest that CIMS has relatively modest metabolic effects that occur primarily during initial stress exposure. These results support the hypothesis that the metabolic consequences of chronic stress vary with stress intensity and/or frequency.

The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice.

OBJECTIVE: Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested. METHODS: Wild type (WT), SHP liver transgenic (SHP-Tg), and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level and composition, steatosis, and BA metabolism gene expression were evaluated. RESULTS: Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight, but developed hepatic inflammation and had increased ALT. CONCLUSIONS: VSG produces weight loss independent of SHP status. SHP ablation creates a proinflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.

Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications.

Significant comorbidities between obesity-related metabolic disease and stress-related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward-driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the interrelationships between metabolism, stress, and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease.

Loss of melanocortin-4 receptor function attenuates HPA responses to psychological stress.

The melanocortin 4 receptor (MC4R), well-known for its role in the regulation of energy balance, is widely expressed in stress-regulatory brain regions, including the paraventricular nucleus of the hypothalamus (PVH) and the medial amygdala (MeA). In agreement with this, MC4R has been implicated in hypothalamic-pituitary-adrenocortical axis (HPA) regulation. The present work investigated the role of chronic Mc4r function to modulate basal HPA axis tone and to facilitate acute HPA responses to psychological stress, using a novel rat model with Mc4r loss-of-function. In this study, adult male rats were placed into 3 groups (n=15/group) according to genotype [wild-type (WT); heterozygous mutant (HET); and homozygous mutant (HOM)]. Basal (pre-stress) plasma adrenocorticotropic hormone (ACTH) and corticosterone were measured in the AM and PM, and the HPA axis response to restraint was assessed in the AM. Rats were perfused at 2h after restraint to assess the effect of loss of MC4R on stress-induced c-Fos immunolabeling in stress-regulatory brain regions. We find that basal (non-stress) AM and PM plasma ACTH and corticosterone showed a normal diurnal rhythm that was not altered according to genotype. Consistent with this, adrenal and thymus weights were unaffected by genotype. However, the plasma ACTH and corticosterone responses to restraint were significantly reduced by loss of MC4R function. Likewise, stress-induced c-Fos immunolabeling in both PVH and MeA was significantly reduced by loss of Mc4r function. These results support the hypothesis that endogenous MC4R signaling contributes to the HPA axis response to stress. Because MC4R plays a critical role in the regulation of energy balance, the present work suggests that it may also serve as an important communication link between brain metabolic and stress systems.