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Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo

Sigal Fishman^*, Radhika H. Muzumdar, Gil Atzmon^*, Xiaohui Ma^*, Xiaoman Yang^*, Francine H. Einstein and Nir Barzilai^*,1

^* Institute for Aging Research, and Diabetes Research and Training Center, Department of Medicine,

Division of Pediatric Endocrinology, Children’s Hospital at Montefiore,

Department of Obstetrics and Gynecology and Women’s Health at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA

¹Correspondence: Institute for Aging Research, Department of Medicine, Belfer Bldg. #701, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. E-mail: barzilai{at}aecom.yu.edu

Impairment of both insulin and leptin action has been implicated in the pathogenesis of nonalcoholic fatty liver disease. By assessing hepatic triglyceride (TG) stores in response to modulation of leptin action (by leptin infusion), we attempted to determine whether leptin has the major role in hepatic TG accumulation. TG were markedly decreased (by 63%, P<0.05) in young animals treated with leptin. However, this was also associated with improvement in hepatic insulin action (2-fold decrease in HGP during clamp, P<0.05). These effects on hepatic TG stores and insulin action were abolished in old rats who demonstrate leptin resistance. Since these experiments could not discern the role of leptin from the role of hepatic insulin action on hepatic TG stores, we further examined the effect of improvement of hepatic insulin action by visceral fat removal (VF-). Enhancement of hepatic insulin action in old VF-rats was associated with reduced hepatic TG stores (by 64% P<0.01). Because this manipulation may have induced an improvement in leptin action as well, we studied VF removal in a genetically leptin-resistant model (Zucker Diabetic Fatty rats, ZDF). Only in this mode was exclusive improvement of hepatic insulin action by VF removal not associated with reduced hepatic TG stores, suggesting that improved hepatic insulin action is not necessary for modulation of hepatic TG stores. By dissociating action of leptin from that of insulin, we suggest that the failure of leptin action is the major physiological mechanism for hepatic steatosis.—Fishman, S., Muzumdar, R. H., Atzmon, G., Ma, X., Yang, X., Einstein, F. H., Barzilai, N. Resistance to Leptin Action is the Major Determinant of Hepatic Triglyceride Accumulation in vivo.

Key Words: hepatic insulin action • steatosis • metabolic syndrome

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