Adipogenic Capacity and the Susceptibility to Type 2 Diabetes and Metabolic Syndrome

Abstract

Some 50 million Americans carry a diagnosis of metabolic syndrome, a combination of life-shortening disorders including type 2 diabetes (T2D). In both humans and rodents, lipids accumulate in those organs that are most affected in the metabolic syndrome. Ectopic lipid overload may, through the process of lipoapoptosis, disable or destroy normal cardiomyocytes and pancreatic beta cells. It is reasonable to suppose that, in the setting of sustained overnutrition, the ability of fat tissue to store surplus lipids determines whether lipids will overflow into nonadipocytes. This study utilized a transgenic mouse model to determine whether adipocyte storage capacity influences the onset and severity of T2D and other elements of the metabolic syndrome. In this model, adipocytes appear normal on a normal diet but they fail to undergo the hypertrophy or hypoplasia expected with a high-fat diet. In addition to T2D, adipocyte storage capacity was related to lipotoxic cardiomyopathy, another major component of the metabolic syndrome. Normal and db/db mice were made resistant to obesity by over-expressing leptin receptor-b on the aP2-Lepr-b promoter. No changes were noted on a 4% fat diet but, on a 60% fat diet, the transgenic mice resisted diet-induced obesity when constitutive adipocyte-specific over-expression of Lepr-b prevented obesity through the antilipogenic autocrine/paracrine action of leptin on adipocytes. After 8 months on a 60% fat diet, the body fat of transgenic mice was 70% below that of control mice. The fat content of the heart and liver was increased in transgenic mice and they had more marked hyperinsulinemia, suggesting greater insulin resistance. The transgene prevented obesity in db/db mice, an effect ascribed in part to reduced expression of sterol regulatory element binding protein-1c and its target lipogenic enzymes in adipose tissue. Transgenic mice were severely diabetic at age 4-0 weeks before the db/db control mice. Echocardiographic findings of cardiomyopathy were present at age 10 weeks, some weeks before they were apparent in control animals. Histologic studies documented the loss of beta cells and the presence of myocardial fibrosis at least 6 weeks earlier in transgenic mice than in control animals. These findings imply that obesity is a precedent to metabolic syndrome that might encourage more aggressive interventions before clinical disease results from overnutrition. Differences in the expression or function of adipogenic genes may alter susceptibility to diet-induced metabolic syndrome.