High fat diet feeding produces transient, not sustained, ghrelin resistance in reward processing. (#126)
Obese animals become resistant to a number of circulating hormones, the best characterised of which are insulin and leptin. Recently, we described the occurrence of ghrelin resistance in mice fed a high fat diet (HFD) for 12 weeks. Ghrelin is predominately considered a signal of homeostatic hunger; however, it is also involved in the rewarding and motivational aspects of feeding. Consumption of a 10% sucrose solution in satiated mice on a chow diet was significantly supressed in ghrelin knockout (KO) mice compared to wildtype C57black/6 (WT) littermates. Ghrelin KO mice still had a significant preference for sucrose solution over water, indicating that they were not anhedonic, but rather had decreased appetitive drive. We wondered whether this phenomenon would be sensitive to ghrelin resistance. Weekly monitoring of IP ghrelin-induced feeding showed a time-dependant decline in ghrelin’s ability to induce feeding in WT mice eating a HFD, with no response being observed after 3 weeks. At this time point mice were also unresponsive to ICV ghrelin administration, with no increase in feeding and decreased Fos activation in NPY neurons in response to ghrelin, and resistant to ghrelin injected directly into the VTA. Sucrose consumption in WT mice was similarly blunted, with significantly reduced consumption that was no longer different from KO mice, indicating that sucrose consumption may be sensitive to the effects of ghrelin resistance. Mice tested for ghrelin resistance in reward processing after 12 weeks on HFD did not show deficits, however, with reinstatement of increased sucrose consumption and sensitivity to intra VTA ghrelin. These findings indicate that reward pathways may remain sensitive to hormonal signals in the face of significant obesity, even when hypothalamic pathways are resistant to those signals.