ECE2022 Poster Presentations Diabetes, Obesity, Metabolism and Nutrition (202 abstracts)
Background: Leptin reduces hepatic lipid content in lipodystrophic and overweight, relatively hypoleptinemic NAFLD patients. However, the underlying mechanism is unknown. In rodents, the anti-steatotic action of leptin is mediated by an increase in VLDL secretion and depends on an intact vagal innervation of the liver.
Methods: In this randomized, placebo-controlled, crossover trial, we study the effects of a single metreleptin injection (0.1 mg/kg body weight) on VLDL1 secretion and hepatic energy/lipid metabolism in 13 male, overnight-fasted volunteers. VLDL1 secretion rate was determined with an intralipid infusion test 4 hours after injection. Hepatic lipid content and phosphorous metabolites were measured with 1 H/31 P-MRS at baseline and 3h after metreleptin injection. In an additional cohort of 10 overnight-fasted, male subjects, we assessed hepatic VLDL1 secretion after modified sham feeding, an established method to stimulate the vagus nerve, where subjects smell, taste and chew, but do not swallow a standardized test meal. Water was served in the control condition.
Results: VLDL1 triglyceride secretion rate was higher after metreleptin than placebo (360±36 vs. 464±45 mg/h; P= 0.049) without differences in circulating insulin. As a consequence of the prolonged fasting period, we observed a similar increase in plasma NEFA, ketone bodies and acylcarnitines in both conditions. However, the almost uniform, fasting-associated increase in liver fat in the placebo condition (+19% relative to baseline, P= 0.01) was prevented by the metreleptin injection. VLDL1 triglyceride secretion correlated with changes in hepatic lipid content (r=0.5, P= 0.02). Hepatic ATP/Pi ratio and ATP synthesis rate changed similarly after placebo and metreleptin. In the second cohort, plasma pancreatic polypeptide increased after modified sham feeding (+296±109% vs. -4±35% in the placebo condition) indicating that our test meal stimulated the vagus nerve. Similar to metreleptin, vagus nerve stimulation was associated with an increased hepatic VLDL1 triglyceride secretion (244±39 vs. 348±32 mg/h; P= 0.02).
Conclusion: Our study supports the hypothesis that, in humans, leptins anti-steatotic action is mediated by an increase in hepatic triglyceride export independent of food intake via a brain-vagus-liver axis.
21 May 2022 - 24 May 2022