A Transgenic Model of Visceral Obesity and the Metabolic Syndrome

TLDR

Visceral fat amount best predicts obesity’s metabolic risks, and although excess glucocorticoids cause visceral obesity and diabetes, typical obesity shows normal circulating glucocorticoid levels. Local conversion of inactive 11‑keto steroids to active glucocorticoids by adipose‑specific 11β‑HSD‑1 was modeled by generating transgenic mice overexpressing this enzyme at levels seen in obese human adipose tissue. Transgenic mice overexpressing adipose 11β‑HSD‑1 displayed elevated corticosterone, visceral obesity (worsened by a high‑fat diet), insulin‑resistant diabetes, hyperlipidemia, and hyperphagia despite high leptin, supporting a role for adipocyte 11β‑HSD‑1 in visceral obesity and metabolic syndrome.

Abstract

The adverse metabolic consequences of obesity are best predicted by the quantity of visceral fat. Excess glucocorticoids produce visceral obesity and diabetes, but circulating glucocorticoid levels are normal in typical obesity. Glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD-1). We created transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11beta HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.