Deletion of suppressor of cytokine signaling 3 from forebrain neurons delays infertility and onset of hypothalamic leptin resistance in response to a high caloric diet

Abstract

The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protectmicefromdiet-inducedobesity,but the effects on HCD-induced infertility areunknown.Weusedneuron-specificSOCS3knock-outmice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specificSOCS3knock-outmice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out femaleswasdelayedby4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-inducedGnRH/LHsurgewereovercomebyneuron-specificSOCS3knock-out.Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric 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 HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction.