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Am J Physiol Endocrinol Metab (November 2, 2004). doi:10.1152/ajpendo.00203.2004
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Submitted on May 12, 2004
Accepted on October 24, 2004

Molecular evidence supporting the portal theory: A causative link between visceral adiposity and hepatic insulin resistance

Morvarid Kabir1, Karyn J. Catalano1, Suchitra Ananthnarayan1, Stella P. Kim1, Gregg W. Van Citters1, Melvin K. Dea1, and Richard N. Bergman1*

1 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

* To whom correspondence should be addressed. E-mail: rbergman{at}usc.edu.

The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "Portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity versus controls (n=6). Tissue samples were obtained from dogs after 12 weeks of either moderate fat (42% calories from fat; n=6) or control diet (35% calories from fat). Northern-Blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-gamma (PPAR{gamma}). In addition, the ratio for sterol regulatory element binding transcription factor-1 (SREBP-1) tended to be higher in fat fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat fed dogs, liver SREBP-1 expression was increased significantly with a tendency for increased fatty acid binding protein (FABP) expression. In addition, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat fed animals versus controls. Moreover insulin receptor binding was 50% lower in fat fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver are consistent with the portal theory. Further studies will need to be performed to determine if FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity.




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