Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner

Mixed background SHP-/- mice are resistant to diet-induced obesity due to increased energy expenditure caused by enhanced PGC-1 alpha expression in brown adipocytes. However, congenic SHP-/- mice on the C57BL/6 background showed normal expression of PGC-1 alpha and other genes involved in brown adipose tissue thermogenesis. Thus, we reinvestigated the impact of small heterodimer partner (SHP) deletion on diet-induced obesity and insulin resistance using congenic SHP-/- mice. Compared with their C57BL/6 wild-type counterparts, SHP-/- mice subjected to a 6 month challenge with a Western diet (WestD) were leaner but more glucose intolerant, showed hepatic insulin resistance despite decreased triglyceride accumulation and increased beta-oxidation, exhibited alterations in peripheral tissue uptake of dietary lipids, maintained a higher respiratory quotient, which did not decrease even after WestD feeding, and displayed islet dysfunction. Hepatic mRNA expression analysis revealed that many genes expressed higher in SHP-/- mice fed WestD were direct peroxisome proliferator-activated receptor alpha (PPAR alpha) targets. Indeed, transient transfection and chromatin immunoprecipitation verified that SHP strongly repressed PPAR alpha-mediated transactivation. SHP is a pivotal metabolic sensor controlling lipid homeostasis in response to an energy-laden diet through regulating PPAR alpha-mediated transactivation. The resultant hepatic fatty acid oxidation enhancement and dietary fat redistribution protect the mice from diet-induced obesity and hepatic steatosis but accelerate development of type 2 diabetes.-Park, Y. J., S. C. Kim, J. Kim, S. Anakk, J. M. Lee, H-T. Tseng, V. Yechoor, J. Park, J-S. Choi, H. C. Jang, K-U. Lee, C. M. Novak, D. D. Moore, and Y. K. Lee. Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner. J. Lipid Res. 2011. 52: 2234-2244.