Leptin decreases de novo lipogenesis in patients with lipodystrophy

Ranganath Muniyappa,Peter J Walter,Majid M Syed-Abdul,Stephanie T Chung,Khaled Z Abd-Elmoniem,Megan Startzell,Ahmed M Gharib,Shaji Chacko,Mary Walter,Ronald Ouwerkerk,Robert Shamburek,Elaine Cochran,Rebecca J Brown,Annah P Baykal,Elizabeth J Parks

doi:10.1172/jci.insight.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.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States [1], and NAFLD progressing to nonalcoholic steatohepatitis is estimated to overtake hepatitis C as the primary cause of liver transplantation in the United States [2]
The percentage of TG-rich lipoproteins (TRLPs)-TG that was derived from de novo lipogenesis (DNL) (%DNL) decreased from a baseline of 20.9% [18.0, 29.7] to 7.3% [5.8, 11.6] (P < 0.001; Figure 1B)
This study demonstrates elevated fasting DNL in patients with lipodystrophy that decreased after 6 months of metreleptin treatment

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States [1], and NAFLD progressing to nonalcoholic steatohepatitis is estimated to overtake hepatitis C as the primary cause of liver transplantation in the United States [2]. Leptin replacement in leptin-deficient rodents reduces hepatic steatosis by decreasing DNL [4]; by contrast, rodent studies suggest that high leptin levels in obesity might contribute to hepatic fibrosis [5, 6]. NAFLD is observed in both the hyperleptinemic state of obesity and the leptin-deficient state of lipodystrophy [7, 8]. Lipodystrophy syndromes are associated with low circulating leptin levels due to low adipose mass, and these syndromes serve as a model to understand effects of leptin deficiency and replacement on metabolic disease. Leptin treatment with recombinant human methionyl leptin (metreleptin) in lipodystrophic patients improves hepatic steatosis and hypertriglyceridemia [9], though the exact mechanisms by which metreleptin mediates these responses have yet to be elucidated.

Methods

Results

Discussion

Conclusion