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 ϭ 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n ϭ 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-␥ (PPAR␥). 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 phosphoenolpyruvate 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. visceral fat; lipolysis; gluconeogenic enzymes; messenger ribonucleic acid; dogs VISCERAL ADIPOSITY HAS BEEN ASSOCIATED with insulin resistance, glucose intolerance, dyslipidemia, and cardiovascular disease (15,18,20). The liver has specifically been implicated as a primary site of insulin resistance observed with visceral obesity. The mechanisms relating visceral fat accumulation and hepatic insulin resistance are not well known, but several possible factors might be implicated. One hypothesis states that visceral fat secretes several substances [tumor necrosis factor-␣ (TNF-␣) (22) and/or resistin (37) or decreased adiponectin (2)] that may induce hepatic insulin resistance. The alternative "portal hypothesis" posits a high rate of lipolysis of visceral adipose tissue leading to increased delivery of free fatty acids (FFA) to the liver via the portal vein, thus contributing to increased fat accumulation and ...

Factors associated with percent change in visceral versus subcutaneous abdominal fat during weight loss: findings from a systematic review

“…In the 'Portal hypothesis' it is suggested that the proximity of VAT lipolysis, hormone and cytokine production upstream from the liver exacerbates hepatic insulin resistance and increases glucose output. 70 VAT appears to further undermine the efficiency of energy metabolism by inducing systemic insulin resistance and influencing a variety of inflammatory pathways. 6,71 Increasing evidence of the biological role of VAT adds greatly to the strength of the conclusion that %dV/%dS is greatest during rapid weight loss with VLCDs or modest weight loss.…”

Mechanisms of obesity-associated insulin resistance: many choices on the menu

“…In addition to states of glucocorticoid excess, visceral adiposity is characteristic of people with an "appleshaped" fat distribution, who appear to have a greater risk of developing insulin resistance than individuals with more peripheral "pear-shaped" fat distribution (Kabir et al 2005). The "portal theory" suggests that insulin resistance in the liver arises from visceral fat drainage directly into the liver via the portal vein (Bergman et al 2007).…”

Adiposidad visceral y su asociación con lípidos séricos e insulinemis en adolescentes obesas

“…grasos libres. Esto puede ir acompañado de una alta producción hepática de glucosa y una disminución en la extracción de insulina por el hígado 14,15 . Se ha encontrado una asociación positiva entre grasa visceral y medidas antropométricas de adiposidad en adolescentes; sin embargo no se ha observado una asociación entre mediciones externas de adiposidad, incluyendo circunferencia de la cintura, con hipercolesterolemia 16,17 .…”