title: Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility.
abstract: The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3.
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Marina O
authors.initials: MO
authors.lastname: Fernandez
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Sun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Emily
authors.initials: E
authors.lastname: Rickert
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hsueh
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Vicky
authors.initials: V
authors.lastname: Hwang
authors.affiliation: Department of Medicine, School of Medicine, and.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.affiliation: Department of Medicine, School of Medicine, and.|Moores Cancer Center, University of California, San Diego, La Jolla, California 92093; and.|Medical Research Service, VA San Diego Healthcare System, San Diego, California 92161.
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D030762:Estrous Cycle; D005260:Female; D005298:Fertility; D005951:Glucose Tolerance Test; D006470:Hemorrhage / Q000473:pathology; D020738:Leptin / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D012741:Sexual Maturation; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism
chemical_list: D020738:Leptin; D047495:PPAR gamma; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein