Fat, carbohydrate, and calories in the development of diabetes and obesity in the C57BL/6J mouse.

We have previously shown that the C57BL/6J (B6) mouse will develop obesity and diabetes if raised on a high-fat diet. Because high fat feeding is associated with hyperphagia, the present study was designed to separate the effects of fat from those of excess caloric consumption in this animal model. B6 mice were fed a low-fat diet (LF group) diet, high-fat diet (HF group) diet, or high-fat-restricted diet (HFR group), in which intake animals were pair-fed a high-fat diet to caloric level consumed by LF for 11 weeks. Within 3 weeks, HFR were significantly heavier than LF and, after 11 weeks, weight and glucose levels, but not insulin, were significantly increased in HFR when compared to LF. Body composition analysis showed the weight increase in HFR arose from an increase in percent fat consumed. We conclude that reducing the number of kilocalories consumed from a high-fat diet attenuates but does not prevent the development of type 2 diabetes and obesity in the B6 mouse.

Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.