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

Young Joo Park, Seong Chul Kim, Jeehee Kim, Sayeepriyadarshini Anakk, Jae Man Lee, Hsiu Ting Tseng, Vijay Yechoor, Junchol Park, June Seek Choi, Hak Chul Jang, Ki Up Lee, Colleen M. Novak, David D. Moore, Yoon Kwang Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Mixed background SHP -/- mice are resistant to diet-induced obesity due to increased energy expenditure caused by enhanced PGC-1α expression in brown adipocytes. However, congenic SHP -/- mice on the C57BL/6 background showed normal expression of PGC-1α 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 β-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 (PPARα) targets. Indeed, transient transfection and chromatin immunoprecipitation verified that SHP strongly repressed PPARα-mediated transactivation. SHP is a pivotal metabolic sensor controlling lipid homeostasis in response to an energy-laden diet through regulating PPARα-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.

Original languageEnglish (US)
Pages (from-to)2234-2244
Number of pages11
JournalJournal of Lipid Research
Volume52
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Hepatic steatosis
  • Insulin sensitivity
  • Oxygen consumption
  • Respiratory quotient
  • β-oxidation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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