Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Abstract

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.

New developments in the biology of fibroblast growth factors

“…Mice deficient for liver FGF21 are partially resistant to glucagon‐receptor‐mediated weight loss, indicating that FGF21 is a regulator of glucagon's weight‐loss effects. Mice deficient for neuronal βKlotho in the brain exhibit a partial reduction in body weight with chronic glucagon‐receptor‐agonism, indicating a role for central FGF21 signaling in glucagon‐receptor‐mediated weight loss (Nason et al, 2021).…”

A GLP‐1/glucagon (GCG)/CCK2 receptors tri‐agonist provides new therapy for obesity and diabetes

“…We observed increased FGF21 levels in xGLP/GCG/gastrin (10 and 25 nmol·kg −1 ), xGLP/GCG‐15 and cotadutide treatment groups, but not in liraglutide and ZP3022 treatment groups (Figure S3A), compared with saline group, which is a selective action of the GCG component within the xGLP/GCG/gastrin, xGLP/GCG‐15 and cotadutide, as previous researchers have indicated in that both acute and chronic GCG receptor activation increase liver FGF21 expression and secretion (Habegger et al, 2013; Kim et al, 2018; Nason et al, 2021). The liver sections stained by H&E revealed that cotadutide, xGLP/GCG‐15 and xGLP/GCG/gastrin (10 and 25 nmol·kg −1 ) normalized hepatic lipid contents to a low level, whereas liraglutide and ZP3022 only decreased hepatic lipid contents to a medium level (Figure 6).…”

“…Means ± SD, n = 6. *P < 0.05 versus saline, a P < 0.05 versus liraglutide, cotadutide and ZP3022 expression and secretion(Habegger et al, 2013;Kim et al, 2018;Nason et al, 2021). The liver sections stained by H&E revealed that cotadutide, xGLP/GCG-15 and xGLP/GCG/gastrin (10 and 25 nmolÁkg À1 ) normalized hepatic lipid contents to a low level, whereas liraglutide and ZP3022 only decreased hepatic lipid contents to a medium level (Figure6).…”

Is Glucagon Receptor Activation the Thermogenic Solution for Treating Obesity?

“…The GCGR is expressed by hepatocytes ( 5 ), where in addition to regulating hepatic glucose production, GCGR signaling reduces liver fat content by inducing lipid oxidation, augmenting metabolic enzyme activity, enhancing mitochondrial function, and increasing liver-specific metabolic rate ( 54 , 78 – 80 ). The importance of the liver in mediating the anti-obesity action of glucagon administration is exemplified by findings in liver-specific knockout models, where the absence of the GCGR ablates the ability of glucagon to induce weight loss ( 54 , 81 ). Together, these studies demonstrate that glucagon action augments energy expenditure and drives weight loss by GCGR activation in the liver; mechanistically, this is due to farnesoid X receptor (FXR)-mediated hepatic futile cycling (see Box 2 ), the secretion of the hepatokine fibroblast growth factor 21 (FGF21) and an induction of plasma levels of bile acid (BA) species known to impact energy homeostasis ( 54 , 63 ).…”

“…In addition to its effect on BAs/FXR, glucagon rapidly and dose-dependently increases hepatic mRNA expression and circulating levels of the thermogenic hormone FGF21 in mice and adult humans ( 63 , 84 ). Notably, FGF21 and the FGF21 receptor complex (FGFR1c and KLB) knockout mouse models indicate that glucagon requires the FGF21 pathway to protect from obesity ( 54 , 63 , 81 ). Mechanistically, FGF21 acts via both central and peripheral mechanisms to leverage the energy-burning power of white and brown adipose tissue to augment metabolic rate in both a UCP1-dependent and -independent manner [see Box 2 ( 85 – 88 )].…”