Orphan nuclear hormone receptor Small Heterodimer Partner plays a protective role in diet‐induced islet dysfunction

Abstract

Our early study found that deficiency of small heterodimer partner (SHP, NR0B2) protected the mice from diet‐induced obesity due to increased fatty acid oxidation but exacerbated glucose tolerance due to impaired glucose‐stimulated insulin secretion upon a 6‐month western diet regimen. Current study explored potential roles of SHP in the development of glucose intolerance furthermore. We assessed islet function using illumina beadchip array and morphometric measurement of pancreatic sections. Beadchip array revealed that many exocrine specific genes (for example, CUB and Zona Pellucida‐Like Domains (cuzd1), pancreas specific transcription factor 1a (ptf1a), trypsin 4 (try4) and pancreatic carboxyl ester lipase (cel) etc.) were markedly down‐regulated in the islets of SHP null mice in either chow or western diet‐fed condition. However, expression of major genes involved in insulin secretion and islet function were similar between WT and SHP null mice. Results from quantitative real‐time PCR analysis agreed with majority of beadchip array results except Glut2, which was decreased in SHP null islets. Corroborating with impaired insulin secretion and lower Glut2 mRNA level, glucose‐stimulated Ca2+ influx was greatly diminished in SHP null islets. Islet size was also decreased in SHP null mice fed either diet. The observed diabetic phenotype and pancreatic exocrine insufficiency in whole body SHP−/−mice was recapitulated in the pancreas specific SHPKO (PSHPKO) mice, where SHP deletion is confirmed in both endocrine and exocrine tissues. Interestingly the lean phenotype was reproduced only in liver‐specific SHPKO mice but not in PSHPKO mice. Even though detailed underlying molecular mechanisms for the observed phenotypes by SHP deletion remain to be elucidated, current data suggest that SHP plays distinctive and tissue‐specific role in the development of obesity and diabetes.Support or Funding InformationThis work had been supported by the National Institutes of Health 344 Grant R01DK093774 (to YKL)