Deletion of suppressor of cytokine signaling 3 from forebrain neurons delays infertility and onset of hypothalamic leptin resistance in response to a high fat and high sucrose diet
McEwan, Hayden; Inglis, Megan; Quennell, Janette; Grattan, David; Anderson, Greg
The cellular processes that cause high fat and sugar diet-induced infertility are poorly understood, but may involve up-regulation of suppressor of cytokine signalling (SOCS-3) proteins which leads to hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on diet-induced infertility are unknown. We utilized neuron-specific SOCS3 knockout mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knockout mice were protected from high fat and sucrose diet (HFD)-induced obesity. Female knockout mice did not become infertile after 4 months of HFD feeding as did their wild-type counterparts, and also did not exhibit leptin resistance onset in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) that induces ovulation. We therefore tested whether the suppressive effects of HFD on the estradiol-induced GnRH/LH surge suppression were overcome by neuron-specific SOCS3 knockout. While only 20% of control HFD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knockout mice on this diet. In contrast to females, HFD-fed male mice did not exhibit any decline in fertility compared to low fat and sucrose diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HFD-fed female mice, but given continued HFD feeding this state does eventually occur, presumably in response to other leptin inhibitory mechanisms.
Publisher: Society for Neuroscience
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Research Type: Journal Article
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