ECE2022 Poster Presentations Diabetes, Obesity, Metabolism and Nutrition (202 abstracts)
Leptin increases VLDL triglyceride secretion and reduces hepatic lipid content in lean male subjects
Matthaeus Metz 1 , Marianna Beghini 1 , Lorenz Pfleger 1 , Peter Wolf 2 , Magdalena Bastian 2 , Jürgen Harreiter 3 , Sabina Baumgartner-Parzer 2 , Rodrig Marculescu 4 , Michael Krebs 2 , Martina Hackl 1 , Michael Trauner 5 , Martin Krssak 3 , Herbert Stangl 6 , Alexandra Kautzky-Willer 7 , Clemens Fürnsinn 3 & Thomas Scherer 1
1Medical University of Vienna, Division of Endocrinology and Metabolism, Vienna, Austria; 1Medical University of Vienna, Division of Endocrinology and Metabolism, Vienna, Austria; 1Medical University of Vienna, Division of Endocrinology and Metabolism, Vienna, Austria; 4Medical University of Vienna, Department of Laboratory Medicine, Vienna,; 5Medical University of Vienna, Division of Gastroenterology and Hepatology, Vienna, Austria; 6Medical University of Vienna, Institute of Medical Chemistry, Vienna, Austria; 7Medical University of Vienna, Department of Medicine III, Division of Endocrinology & Metabolism, Vienna, Austria
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, leptin’s anti-steatotic action is mediated by an increase in hepatic triglyceride export independent of food intake via a brain-vagus-liver axis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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