title: Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner.
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.
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX and.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Seong Chul
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Jeehee
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX and.
authors.forename: Sayeepriyadarshini
authors.initials: S
authors.lastname: Anakk
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX and.
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX and.
authors.forename: Hsiu-Ting
authors.initials: HT
authors.lastname: Tseng
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Vijay
authors.initials: V
authors.lastname: Yechoor
authors.affiliation: Department of Psychology, Korea University, Seoul, Korea.
authors.forename: Junchol
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Psychology, Korea University, Seoul, Korea.
authors.forename: June-Seek
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Hak Chul
authors.initials: HC
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea; and.
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, OH.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Novak
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX and. Electronic address: moore@bcm.tmc.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX and. Electronic address: ylee3@neomed.edu.
authors.forename: Yoon Kwang
authors.initials: YK
authors.lastname: Lee
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology; D000818:Animals; D001481:Basal Metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D005786:Gene Expression Regulation; D018149:Glucose Intolerance; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D010100:Oxygen