@article{10.1172/jci.insight.137180, author = {Annah P. Baykal AND Elizabeth J. Parks AND Robert Shamburek AND Majid M. Syed-Abdul AND Shaji Chacko AND Elaine Cochran AND Megan Startzell AND Ahmed M. Gharib AND Ronald Ouwerkerk AND Khaled Z. Abd-Elmoniem AND Peter J. Walter AND Mary Walter AND Ranganath Muniyappa AND Stephanie T. Chung AND Rebecca J. Brown}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Leptin decreases de novo lipogenesis in patients with lipodystrophy}, year = {2020}, month = {7}, volume = {5}, url = {https://insight.jci.org/articles/view/137180}, abstract = {De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.}, number = {14}, doi = {10.1172/jci.insight.137180}, url = {https://doi.org/10.1172/jci.insight.137180}, }