FGF21/Leptin Dual Agonist Reverses Hepatic Leptin Resistance, Protecting Mice from Diet-Induced Obesity and Metabolic Comorbidities
Background
The global obesity epidemic is often complicated by leptin resistance, a key barrier to effective therapeutic intervention for metabolic comorbidities. While leptin is a crucial satiety hormone, its efficacy is blunted in obese states due to impaired signaling. Fibroblast growth factor 21 (FGF21) is an endocrine hormone known for its pleiotropic metabolic effects, primarily through FGFR1c and β-Klotho. Understanding how FGF21 interacts with leptin signaling, particularly in overcoming resistance, could unlock novel strategies for treating metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and other related conditions.
Study Design
Researchers investigated the synergistic effects of FGF21 and leptin using a long-acting FGF21/leptin dual agonist in diet-induced obese mice. The dual agonist was administered via intraperitoneal injection, and its pharmacological effects were compared against FGF21 mono-agonist and leptin mono-agonist treatments. Primary endpoints included protection from weight gain, insulin resistance, hyperglycemia, dyslipidemia, and MASLD. Additionally, human primary hepatocytes and liver organoids were used to study the impact of adiponectin and FGF21 on palmitate/oleate-induced downregulation of leptin receptor b and its subsequent effects on gluconeogenesis and hepatic steatosis.
Results
FGF21 was found to synergize with leptin in metabolic regulation by reversing obesity-induced peripheral leptin resistance. This mechanism involves FGF21 acting in adipocytes to promote the secretion of adiponectin. Adiponectin, in turn, induces the expression of leptin receptors in hepatocytes through the phosphorylation and activation of signal transducer and activator of transcription 1 (STAT1).
Intraperitoneal injection of the long-acting FGF21/leptin dual agonist achieved much more robust pharmacological effects than either FGF21 or leptin mono-agonists in protecting mice from diet-induced weight gain, insulin resistance, hyperglycemia, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease.
Key Findings
- FGF21 synergizes with leptin to improve metabolic regulation by reversing obesity-induced peripheral leptin resistance.
- FGF21 promotes adiponectin secretion from adipocytes, which induces leptin receptor expression in hepatocytes.
- Adiponectin's action on leptin receptors is mediated by phosphorylation and activation of
STAT1in hepatocytes. - A long-acting FGF21/leptin dual agonist robustly protected mice from diet-induced weight gain, insulin resistance, hyperglycemia, dyslipidemia, and MASLD.
- The dual agonist achieved these effects without altering food intake in mice.
Why It Matters
This research highlights a promising therapeutic avenue for obesity-related multimorbidity by addressing a core challenge: leptin resistance. By leveraging the synergistic actions of FGF21 and leptin, a dual agonist could offer superior metabolic benefits compared to single-agent therapies, potentially leading to more effective weight management and resolution of conditions like MASLD and insulin resistance. The finding that the dual agonist did not affect food intake suggests a mechanism beyond appetite suppression, which could be beneficial for patients struggling with metabolic dysfunction independent of caloric restriction. This preclinical work lays the groundwork for developing novel compounds that combine these two powerful metabolic regulators.
fgf21
leptin
obesity
masld
insulin-resistance
dyslipidemia