Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon’s weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.
Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in diet-induced obese (DIO) mice. Glucagon’s role as a primary counterregulatory hormone to insulin action has long received scientific attention, yet its broader therapeutic potential is an evolving research interest. We reported that chronic glucagon receptor (GCGR) activation increased energy expenditure and plasma bile acids (BA) in an farnesoid X receptor (FXR) dependent manner. Glucagon stimulates the conversion of cholesterol to BAs, with an increase in cholic and chenodeoxycholate species, critical regulators of FXR activity. Gut microbiota are known to alter the chemical structure of bile acids to produce secondary and tertiary BA. Thus, in these studies we tested the hypothesis that GCGR agonism regulates the gut microbiome to alter circulating BAs and stimulate FXR. GCGR agonism stimulated a profound change in the gut microbiome of DIO mice. These changes were largely associated with an increase in Actinobacteria and a decrease in Deferribacteria phylums. Assessment of functional microbiome composition via PICRUSt uncovered significant impacts on 130 out of 160 total KEGG pathways, including those involved in BA synthesis. To investigate the role of the gut microbiome on GCGR-stimulated weight loss we treated DIO mice with an antibiotic (AB) cocktail (ampicillin, vancomycin, metronidazole, neomycin, and amphotericin B) or vehicle. Mice were then treated with the GCGR agonist, IUB288, or vehicle for 14d to stimulate weight-loss. Surprisingly, AB-treated mice lost a similar amount of body-weight when treated with IUB288, suggesting that the gut microbiome may be dispensable for the weight loss effect. However, post hoc analysis of the cecal microbiome identified only a partial ablation of microbiota in AB-treated mice, with unexpected increases in Proteobacteria and Tenericutes. Thus, it is possible that GCGR-agonism acts via one of the resistant microbes to regulate weight loss. Disclosure T. Kim: None. J.P. Antipenko: None. S. Nason: None. N. Presedo: None. W.J. Van Der Pol: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. C.D. Morrow: None. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc. Funding National Institutes of Health
Glucagon is an essential regulator of glucose and lipid metabolism. We have reported that chronic glucagon receptor (GCGR) activation with the highly selective, long-acting GCGR-agonist, IUB288, promotes weight-loss by stimulating energy expenditure and suppressing food intake in diet-induced obese (DIO) mice. Thus, novel therapeutics that include glucagon receptor (GCGR) agonism have emerged as promising candidates for obesity and diabetes. GCGR-stimulated energy expenditure is predominately dependent on hepatic GCGR activation; however, the tissue(s) responsible for GCGR-dependent suppression of food intake have yet to be elucidated. Intriguingly, intracerebroventricularly (ICV) injected glucagon acutely suppresses food intake, suggesting neurons expressing GCGR in the brain mediate the anorectic actions of GCGR activation. Hypothalamic neurons express appetitive neuropeptides, sense nutrients in circulation, and respond to peripheral endocrine signals. Studies herein, utilize mice with hypothalamic Gcgr-deficiency (GcgrΔHypo) to test the hypothesis that peripherally administered GCGR-agonists (e.g. IUB288) reverse obesity via their actions on hypothalamic GCGRs to suppress food intake and concurrent hepatic effects on energy expenditure. GcgrΔHypo and littermate control mice were fasted overnight to stimulate endogenous hunger signals and test for differential food intake upon refeeding. Interestingly, lean, male GcgrΔHypo mice displayed acute hyperphagia in comparison to control littermates. GcgrΔHypo mice also displayed elevated locomotor activity, an increase in the respiratory exchange ratio, and elevated energy expenditure compared to littermate controls. Furthermore, these metabolic alterations are associated with delayed body weight gain and chronic hyperphagia in GcgrΔHypo mice allowed ad libitum access to a high fat diet for 12 weeks. Consistent with our hypothesis, chronic peripheral administration of IUB288 (14d i.p.) suppressed food intake in DIO male control, but not GcgrΔHypo, mice. Altogether, these data suggest that hypothalamic GCGRs mediate the anorectic actions of GCGR activation and play a regulatory role in food take. Moreover, these findings suggest that GCGR-based therapeutics may act on both intake and expenditure components of energy balance to combat obesity.
Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. Thus, novel therapeutics that stimulate glucagon‐receptor (GCGR) signaling are promising targets for treatment of obesity and diabetes; however, the mechanism(s) underlying these effects are yet to be fully elucidated. We previously identified that hepatic glucagon signaling increases the secretion of Fibroblast Growth Factor 21 (FGF21), a fasting hormone that regulates energy balance. We have recently observed that mice deficient for liver Fgf21 are partially resistant to the anti‐obesity effects of GCGR agonism, implicating hepatic FGF21 as an essential component of glucagon’s weight‐loss effects. FGF21 signals through the canonical FGF‐receptors coupled with an obligate co‐receptor (bKlotho, Klb). Expression of KLB, and therefore FGF21 signaling, is limited to adipose tissue, liver, and brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus and the hindbrain. The hypothalamus is a critical regulator of energy balance; thus, we hypothesized that the anti‐obesity action of the glucagon‐FGF21 system signals through a central mechanism. To test this hypothesis, we generated mice with neuronal Klb deficiency (Klbflox x Synapsin1Cre: KlbΔCNS). KlbΔCNS mice are less susceptible to diet‐induced obesity than control mice (p<0.01), with no differences in food intake or energy expenditure. Following chronic GCGR activation via the selective GCGR agonist IUB288, KlbΔCNS mice exhibit a partial reduction in body weight (11%) in comparison to control mice (18%) (p<0.001), suggesting that FGF21 mediates glucagon’s anti‐obesity properties through central action. Similar to the congenital knockout, wildtype mice treated with a selective KLB antagonist via intracerebroventricular administration also exhibited partial reductions in body weight following chronic IUB288 treatment. Consistent with GCGR‐stimulated, neuronal FGF21 signaling, we found that neuronal activation, measured via cFos expression, was increased in the SCN following IUB288 injection. To further interrogate SCN‐specific FGF21 signaling, we generated mice with SCN‐specific Klb deficiency (KlbΔSCN) via targeted adenoviral Cre recombinase induction. KlbΔSCN mice display an increase in food intake, body, and fat mass compared to control mice. Changes in food intake were associated with an increase in both light‐ and dark‐phase feeding for KlbΔSCN mice compared to controls (p<0.001). Future studies will aim to continue to interrogate SCN‐specific FGF21 signaling via the pharmaceutical antagonist and the KlbΔCNS model. Taken together, these data suggest that 1) KLB/FGF21 signaling of the SCN is critical for normal energy balance and 2) glucagon mediates part of its anti‐obesity properties through FGF21‐KLB signaling in the CNS. In sum, these findings provide insight for future treatments against obesity and the metabolic syndrome. Support or Funding Information The project described was supported by the NIH grant 1R01DK112934.
Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in obese mice. We have shown that hepatic Farnesoid X Receptor (FXR, a bile acid receptor) and bile acids (BA) play an important role in the anti-obesity effect of glucagon in mice. Specifically, glucagon-receptor (GCGR) agonism is a potent regulator of BA metabolism, increasing total plasma BA levels and preferentially raising cholic and chenodeoxycholic acid levels. These findings led us to hypothesize that BA, signaling via hepatic FXR, contributes to GCGR-stimulated weight loss. Furthermore, we reasoned that BA sequestration may impair GCGR-mediated weight loss by reducing the availability of BA to stimulate FXR-action. Thus, to elucidate the role of BA in GCGR-mediated weight loss, we utilized anion-exchange BA-binding resins (BARS; Cholestyramine and Colesevelam) to prevent intestinal (ileal) re-uptake and reduce plasma total cholesterol, LDL, and BAs via fecal excretion. Diet-induced obese (DIO) C57Bl/6J mice were randomized to groups matched for body-weight and administered daily GCGR agonism (IUB288, 10 nmol/kg, s.c.) or vehicle, in the presence or absence of BARS. Consistent with our prior findings, IUB288-treatment reduced body weight in DIO mice. Counter to our original hypothesis, IUB288+Cholestyramine (3% in high fat diet, HFD [58% kcal%]) enhanced IUB288-stimulated weight loss. Similar body-weight loss effects following combined IUB288 and BARS treatment were replicated both at a lower dose of Cholestyramine (1.5% in HFD), as well as in combination with both low- (2% in HFD) and high- (4% in HFD) dose Colesevelam. IUB288-stimulated weight loss is accompanied by suppression of food intake (FI), while Colesevelam alone did not significantly lower FI at either dose (2 or 4% in HFD). However, 4% Colesevelam with IUB288 completely suppressed FI, while 2% Colesevelam stimulated a reduced, though not complete suppression. GCGR agonism is a potent stimulus of weight loss; however, its impairment of glucose tolerance reduces its value as a monotherapy. Excitingly, Cholestyramine (3% in HFD) rescued IUB288-induced glucose intolerance, restoring glucose excursion to levels observed in control (vehicle-treated) mice. Together these studies suggest BARS may enhance the anti-obesity effect of GCGR agonism, beneficially regulate feeding behaviors, and prevent GCGR-stimulated glucose dysregulation in DIO mice. Furthermore, these studies argue that GCGR agonsim combined with BARS treatment may represent a novel therapeutic approach for obesity and obesity-associated glucose intolerance.
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