Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.

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We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.