Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice

High fat diet (HFD)-feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After three weeks of HFD-feeding, neither peripheral nor central ghrelin increased food intake and or activated NPY neurons as demonstrated by a lack of Fos-immunoreactivity or whole-cell patch clamp electrophysiology. Pair-feeding studies that matched HFD calorie intake with chow calorie intake show that HFD exposure does not cause ghrelin resistance independent of body weight gain. We observed increased plasma leptin in mice fed a HFD for 3 weeks and show that leptin-deficient obese ob/ob mice are still ghrelin-sensitive but become ghrelin-resistant when central leptin is co-administered. Moreover, ob/ob mice on a HFD for three weeks remain ghrelin sensitive and the ability of ghrelin to induce action potential firing in NPY neurons was blocked by leptin. We also examined hypothalamic gliosis in mice on a chow or HFD, as well as in ob/ob mice on a chow diet or HFD and lean controls. HFD mice exhibited increased GFAP-positive cells compared with chow-fed mice, suggesting that hypothalamic gliosis may underlie ghrelin resistance. However, we also observed an increase in hypothalamic gliosis in ob/ob mice on HFD diet compared to ob/ob chow-fed and lean controls. Since ob/ob mice on a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pairfeeding HFD to match the calorie intake of chow controls did not increase body weight gain or cause central ghrelin resistance, thus our evidence suggests that diet-induced hyperleptinemia, rather than diet-induced hypothalamic gliosis or HFD exposure, causes ghrelin resistance.