title: Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice.
abstract: The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.
authors.affiliation: Department of Obtetrics and Gynecology, Columbia University, New York, New York 10032, USA. dt2016@columbia.edu
authors.forename: Drew V
authors.initials: DV
authors.lastname: Tortoriello
authors.forename: Julie
authors.initials: J
authors.lastname: McMinn
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
mesh_terms: D000818:Animals; D001823:Body Composition; D004041:Dietary Fats / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D006946:Hyperinsulinism / Q000503:physiopathology; D007031:Hypothalamus / Q000503:physiopathology*; D007247:Infertility, Female / Q000503:physiopathology*; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009478:Neuropeptide Y / Q000235:genetics; D009765:Obesity / Q000503:physiopathology*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D012097:Repressor Proteins / Q000235:genetics; D013045:Species Specificity; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004041:Dietary Fats; D020738:Leptin; D009478:Neuropeptide Y; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors