Leptin decreases de novo lipogenesis in patients with lipodystrophy

Authors: BAYKAL, ANNAH - National Institute Of Diabetes And Digestive And Kidney Diseases; PARKS, ELIZABETH - University Of Missouri; SHAMBUREK, ROBERT - National Heart, Lung And Blood Institute(NHLBI, NIH); SYED-ABDUL, MAJID - University Of Missouri; CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); COCHRAN, ELAINE - National Institute Of Diabetes And Digestive And Kidney Diseases; STARTZELL, MEGAN - National Institute Of Diabetes And Digestive And Kidney Diseases; GHARIB, AHMED - National Institute Of Diabetes And Digestive And Kidney Diseases; OUWERKERK, RONALD - National Institute Of Diabetes And Digestive And Kidney Diseases; ABD-ELMONIEM, KHALED - National Institute Of Diabetes And Digestive And Kidney Diseases; WALTER, PETER - National Institute Of Diabetes And Digestive And Kidney Diseases; MUNIYAPPA, RANGANATH - National Institute Of Diabetes And Digestive And Kidney Diseases; CHUNG, STEPHANIE - National Institute Of Diabetes And Digestive And Kidney Diseases; BROWN, REBECCA - National Institute Of Diabetes And Digestive And Kidney Diseases

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/10/2020
Publication Date: 6/23/2020
Citation: Baykal, A.P., Parks, E.J., Shamburek, R., Syed-Abdul, M.M., Chacko, S., Cochran, E., Startzell, M., Gharib, A.M., Ouwerkerk, R., Abd-Elmoniem, K.Z., Walter, P.J., Muniyappa, R., Chung, S.T., Brown, R.J. 2020. Leptin decreases de novo lipogenesis in patients with lipodystrophy. Journal of Clinical Investigation. 5(14):e137180. https://doi.org/10.1172/jci.insight.137180.
DOI: https://doi.org/10.1172/jci.insight.137180

Interpretive Summary: Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in the United States, and its progress to nonalcoholic steatohepatitis is estimated to overtake hepatitis C as the primary cause of liver transplantation in the United States. One source of triglyceride in the liver is via the synthesis of fatty acids from nonlipid, primarily carbohydrate, precursors. The objective of this research was to determine whether recombinant leptin (metreleptin) treatment in patients with lipodystrophy would reduce fat synthesis by decreasing insulin resistance and high blood glucose. Scientists in Houston, Texas demonstrated that 6 months of metreleptin treatment in very insulin-resistant humans with lipodystrophy led to near normalization of fatty acid synthesis. Improvements in fat synthesis in the liver were associated with reductions in blood glucose and improved insulin sensitivity. Our findings indicate that metreleptin treatment lowered hepatic steatosis and dyslipidemia and suggests that treatments targeting multiorgan insulin resistance may improve nonalcoholic fatty liver disease.

Technical 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 X %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 leptinmediated 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.