Evidence That Diet-Induced Hyperleptinemia, but Not Hypothalamic Gliosis, Causes Ghrelin Resistance in NPY/AgRP Neurons of Male Mice

Abstract

High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-related peptide neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After 3 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 coadministered. Moreover, ob/ob mice fed a HFD for 3 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 fed a chow diet or HFD, as well as in ob/ob mice fed a chow diet or HFD and lean controls. HFD-fed mice exhibited increased glial fibrillary acidic protein-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 fed a HFD compared with chow-fed ob/ob and lean control mice. Because ob/ob mice fed a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pair-feeding a HFD to match the calorie intake of chow-fed 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.

Diet-induced obesity causes ghrelin resistance in reward processing tasks

“…Presumably ghrelin is part of the metabolic signal that communicates homeostatic information to mesolimbic dopaminergic pathways . Our results, together with previously published reports of ghrelin resistance in NPY/AgRP neurons (Briggs et al, 2010;Briggs et al, 2014) support the concept that DIO broadly initiates ghrelin resistance in the brain. The physiological relevance of ghrelin resistance may represent a mechanism that protects a higher body weight set point established by HFD.…”

“…Subsequent time course studies show that this ghrelin resistance occurs after just 3 weeks exposure to HFD (Briggs et al, 2014)and that ghrelin resistance was reversible after diet-restricted weight loss (Briggs et al, 2013). In this study, we determined if HFD causes ghrelin resistance in the VTA, a key nodefor reward processing.…”

“…These deficits occur after several weeks of HFD feeding (Briggs et al, 2014), and persist while body weight remains high, but can be reversed with dietinduced weight loss (Briggs et al, 2013). Others have recently demonstrated ghrelin resistance in the vagal afferents and nodose ganglion, suggesting that this phenomenon is not limited to the hypothalamus (Naznin et al, 2015).…”

Palatability Can Drive Feeding Independent of AgRP Neurons

“…While control animals exhibited a more robust increase in feeding response to ghrelin after 2 weeks of HFHS-diet exposure, the responses of both groups were identical after 10 weeks of HFHSdiet exposure. This result is consistent with the observation that diet-induced obesity leads to ghrelin resistance (Briggs et al, 2010;Briggs et al, 2014) and suggests that diet-induced obesity promotes a phenotype similar to that achieved with loss of AgRP neurons.…”

Impaired oxidative capacity due to decreased CPT1b levels as a contributing factor to fat accumulation in obesity

“…One study showed that feeding a high-fat diet overnight before central ghrelin administration was sufficient to blunt the orexigenic effects of ghrelin, suggesting that the diet interferes with ghrelin signaling (42). However, others find that longer time periods and increased body weight are necessary before ghrelin resistance occurs (6). Thus the underlying cause, e.g., the diet or the resultant obesity, is not fully understood.…”