FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia

Abstract

Despite their different physiologic functions as hormonal regulators of fed and fasted metabolism, pharmacologic administration of FGF19 and FGF21 similarly cause increases in energy expenditure, weight loss and enhanced insulin sensitivity in obese animals. Here, in genetic loss-of-function studies of the shared co-receptor β-Klotho, we show these pharmacologic effects are mediated through a common tissue-specific pathway. Surprisingly, FGF19 and FGF21 actions in liver and adipose tissue are not required for their longer-term weight loss and glycemic effects. In contrast, β-Klotho in neurons is essential for both FGF19 and FGF21 to cause weight loss and lower glucose and insulin levels. We further show that an FGF21 mimetic antibody that activates the FGF receptor 1/β-Klotho complex also requires neuronal β-Klotho for its metabolic effects. These studies highlight the importance of the nervous system in mediating the beneficial weight loss and glycemic effects of endocrine FGF drugs.

Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes

“…Protein restriction increases energy expenditure Earlier studies showed that FGF21 is required for low-protein-induced changes in energy expenditure, and that pharmacological FGF21 treatment acts in the brain and directly on adipose tissue to increase energy expenditure [3,6,12]. To test whether the energy expenditure might be different between the two low-protein groups despite a hyperphagic response, and explain the hyperglycaemia in LP/HC mice, energy expenditure was measured at the beginning and end of the study.…”

“…Administration of FGF21 to mice induces activation of brown adipose tissue (BAT), and increases energy expenditure and insulin sensitivity [9][10][11]. The nervous system is the direct target of FGF21, whereas β-Klotho in adipose tissue and liver is dispensable for FGF21 effects on weight loss [12]. Furthermore, FGF21 improves beta cell function and survival [13], and prevents pancreatic inflammation [14].…”

HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

“…The liver undergoes a postprandial metabolic reprogramming to assimilate the glucose and triggers liver–brain–periphery axis to turn off the fat utilization (Izumida et al , ). Hepatokine fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by various metabolic stresses, including fasting, high‐carbohydrate diets and exercise that regulates energy homeostasis(Gaich et al , ; Galman et al , ; Kim et al , ,b; Lan et al , ; Solon‐Biet et al , ). The transgenic overexpression FGF21 mice showed female infertility and circadian behavior disruption (Bookout et al , ; Owen et al , ), and FGF21 treatment has also been shown to modulate the growth hormone, insulin‐like growth factor 1 (IGF1) axis, and stimulate bone loss (Talukdar et al , ; Wang et al , ; Wei et al , ; Zhang et al , ).…”

Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes

“…An interesting potential translational application to consider would be other causes of microvesicular steatosis, such as Reye syndrome or acute fatty liver of pregnancy; however, this speculation will require formal experimental validation. Further mouse studies have highlighted alternative pathways for FGF19 signaling in metabolic regulation by demonstrating that liver‐specific signaling is not required but rather that neuronal signaling mediates long‐term metabolic effects on body weight and glycemic control …”