Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome.
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.
Wang
May-Yun
MY
Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA.
Grayburn
Paul
P
Chen
Shuyuan
S
Ravazzola
Mariella
M
Orci
Lelio
L
Unger
Roger H
RH
D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005934:Glucagon / Q000032:analysis / Q000378:metabolism; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics*; D010179:Pancreas / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D054411:Receptors, Leptin; D051780:Sterol Regulatory Element Binding Protein 1; C515447:leptin receptor, mouse; D005934:Glucagon