LEAP2 acts in hepatocytes and at central level, alleviates steatosis and inflammation but resistance in obese and aging.

LEAP2 inhibited lipid accumulation in human and mouse hepatocyte cultures.

• LEAP2 actions on hepatocyte lipid metabolism were investigated using both human and mouse hepatocyte cultures.
• LEAP2 directly acted at the hepatocyte level to reduce lipid accumulation.
• This finding identifies LEAP2 as a novel regulator of hepatic lipid metabolism.

Chronic central administration of LEAP2 reduced hepatic lipid deposition in mice fed a standard diet.

• In vivo studies were conducted using chronic central (intracerebroventricular) LEAP2 administration in mice.
• LEAP2 reduced hepatic lipid deposition in animals maintained on a standard diet.
• This indicates LEAP2 acts both at the hepatocyte level and centrally to regulate liver lipid metabolism.

LEAP2 did not prevent high-fat diet-induced steatosis in young obese mice, although it attenuated hepatic inflammation.

• Young mice fed a high-fat diet received chronic central LEAP2 administration.
• LEAP2 failed to prevent the development of diet-induced hepatic steatosis in this model.
• Despite the lack of effect on steatosis, LEAP2 did attenuate hepatic inflammation in high-fat diet-fed young mice.
• These results suggest a resistance to LEAP2's anti-steatotic effects in the context of diet-induced obesity.

LEAP2 failed to suppress age-associated inflammation and steatosis in aged animals.

• An age-related steatosis model was used to evaluate LEAP2 efficacy in aged mice.
• Chronic central LEAP2 administration did not reduce hepatic steatosis in aged animals.
• LEAP2 also failed to suppress age-associated hepatic inflammation in aged animals.
• The authors note that 'LEAP2's effects on age-related steatosis appear limited,' suggesting an aging-related resistance to LEAP2 signaling.

MAFLD affects over 30% of the population, making it the most prevalent liver disorder worldwide.

• The global increase in obesity and metabolic syndrome has driven a rise in liver disease comorbidities.
• Hepatic steatosis, the hallmark of MAFLD, can progress to inflammation, fibrosis, steatohepatitis, and cirrhosis.
• Despite advances in understanding its mechanisms, no effective pharmacological therapy exists to reverse disease progression.

LEAP2 has been identified as an endogenous ghrelin receptor antagonist and inverse agonist with implications for energy and lipid homeostasis.

• LEAP2 is a liver-expressed antimicrobial peptide 2 that acts as an endogenous antagonist and inverse agonist of the ghrelin receptor.
• The ghrelin signaling axis has been implicated in energy and lipid homeostasis.
• The identification of LEAP2 as a ghrelin receptor antagonist generated interest in its potential role in liver metabolism.
• Targeting the LEAP2-ghrelin axis is proposed as a 'promising therapeutic strategy' for liver disease.