Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome

Abstract

To determine whether adipocyte storage capacity influences the onset and severity of type 2 diabetes and other components of the metabolic syndrome, we made normal and db/db mice resistant to obesity by overexpressing leptin receptor-b on the aP2-Lepr-b promoter. On a 4% diet, these mice have no phenotype, but on a 60% fat diet, they resist diet-induced obesity because constitutive adipocyte-specific overexpression of Lepr-b prevents obesity via the antilipogenic autocrine/paracrine action of leptin on adipocytes. After 8 months on the same 60% fat diet, body fat of transgenic mice was 70% below WT controls. Cardiac and liver fat was elevated in the transgenics, and their hyperinsulinemia was more marked, suggesting greater insulin resistance. The aP2-Lepr-b transgene also prevented obesity in db/db mice; at 10 weeks of age their body fat was half that of the db/db mice. This lack of obesity was attributable to reduced expression of sterol regulatory element binding protein-1c and its target lipogenic enzymes in adipose tissue and a 6-fold increase in Pref-1 mRNA. Severe diabetes was present in transgenics at 4 weeks of age, 10 weeks before db/db controls. Echocardiographic evidence of cardiomyopathy appeared at 10 weeks, weeks before the db/db mice. Histologically, loss of beta cells and myocardial fibrosis was present in the transgenic group at least 6 weeks before the db/db mice. These results suggest that the expression level of genes that regulate the adipogenic response to overnutrition profoundly influences the age of onset and severity of diet-induced type 2 diabetes and co-morbidities.

Fig. 1.

Comparison of 10-week-old db/db, db/db-tg, and normal mice. (A) Exposure of s.c. and visceral fat showing less fat in the db/db-tg mouse. Appearance of both db/db and db/db-tg livers suggests steatosis, which is more marked in the latter. (B) Sections of epididymal fat of db/db, db/db-tg, and WT mice, showing reduced size of db/db-tg adipocytes compared with db/db despite identical food intake (Table 2). Immunoblot for C terminus of mouse Lepr-b is positive in db/db-tg fat but not in db/db fat. (C Upper) Adipose tissue phospho-STAT3, an index of leptin action, in db/db, db/db-tg, and normal mice. (Lower) Bars indicate the mean ± SEM of phospho-STAT3/STAT3 ratios.

Fig. 2.

Clinical evidence that obesity delays the onset of T2D in db/db mice. (A) Comparison of nonfasting blood glucose levels in obese db/db and nonobese db/db-tg mice, demonstrating the later appearance of less severe hyperglycemia in the db/db mice. (B and C) Comparison of the cages and the water bottles of 10-week-old obese db/db and nonobese db/db-tg mice, showing evidence of polyuria and polydipsia only in the latter. (D) Comparison of urine glucose testing in obese db/db and nonobese db/db-tg mice (Keto-Diastix Reagent Strip, Bayer, Elkhart, IN), showing glycosuria only in the latter.

Fig. 3.

Immunofluorescent staining for insulin and glucagon of pancreas. (A) Low magnification view of pancreatic tissue showing a large number of islets in db/db mice (Left) and a fewer number of small insulin-positive areas in db/db-tg mice (Right). (B) Higher magnification of the cells in A. (C) The normal topography of glucagon-containing α cells in db/db mice (Left) contrasts with disrupted cells in db/db-tg mice (Right). (Scale bars: 100 μm.)

Fig. 4.

Function and gross and microscopic appearance of the heart of 10-week-old db/db and db/db-tg mice. (A) Echocardiographically measured fractional shortening demonstrating greater functional loss in 10-week-old db/db-tg mice. The dotted line marks the normal value of fractional shortening. (B) Gross enlargement of the heart in a db/db-tg mouse. (C) Myocardium of db/db and db/db-tg mice exhibits myofiber disruption and focal fibrosis in the latter.