Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance
Abstract
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 vs. controls ( n = 6). Tissue samples were obtained from dogs after 12 wk 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-γ (PPARγ). 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 (G-6-Pase) and phospho enolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. 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, is consistent with the portal theory. Further studies will need to be performed to determine whether 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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Recent studies suggest that visceral adiposity may play an important role in causing hepatic insulin resistance through release of fatty acids and adipocytokines to the liver via the portal vein.
“Recent studies have also suggested that visceral adiposity may play an important role in causing hepatic insulin resistance through its release of fatty acids and adipocytokines to the liver via the portal vein (28-31).”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [31]
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- Authors
- Kabir, M., Catalano, K. J., Ananthnarayan, S., Kim, S. P., Van Citters, G. W., Dea, M. K., & Bergman, R. N.
- Affiliations
- University of Southern California (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2005-02
- Volume
- 288
- Issue
- 2
- Pages
- E454-E461
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2106931189
- Cited by
- 327
- References
- 45
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 13 · 2021: 12 · 2020: 9 · 2019: 20 · 2018: 8 · 2017: 18 · 2016: 13 · 2015: 21 · 2014: 17 · 2013: 22 · 2012: 29
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK029867, DK27619, DK29867)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- hepatic insulin resistance, visceral fat, abdominal obesity, lipolysis, lipoprotein lipase, PPARγ, SREBP1, hormone-sensitive lipase, fatty acid binding protein, gluconeogenesis, liver triglyceride accumulation, insulin receptor binding
- MeSH terms
- Adipose Tissue, Animals, Body Constitution, Dietary Fats, Dogs, Gene Expression Regulation, Glucose, Insulin Resistance, Liver, Male, Models, Biological, Organ Specificity, Statistics as Topic, Viscera, Causality, Lipid Metabolism
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