Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons

Abstract

Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.

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.…”

“…Reciprocally, dopamine receptor agonists had a more pronounced satiety action in AgRP-ablated mice compared to controls. Importantly, long-term exposure to HFHS diet which results in ghrelin resistance in AgRP neurons (Briggs et al, 2010) produced a behavioral response to ghrelin similar to that observed in AgRP-ablated mice. Mice lacking AgRP neurons are also more susceptible to both stress-induced anorexia and palatable-diet hyperphagia.…”

Biology's response to dieting: the impetus for weight regain

“…Evidence from human fMRI studies does show weight-reduced subjects have altered neural activity in the brain stem (197), but, unlike other neural responses to weight reduction, this does not normalize with leptin therapy. Taken together, the sensitivity of the brain to gut-derived signals appears to be depressed in the obese (31), but the improved sensitivity after weight loss and during weight regain needs to be confirmed in DIO models of obesity (Fig. 3, A and B).…”

The role of the central ghrelin system in reward from food and chemical drugs

“…Thus, as reviewed elsewhere (Egecioglu et al 2011;Skibicka and Dickson 2011), GHS-R1A provides a potential target for the treatment of problematic over-eating. Indeed, it will be important to establish how the ghrelin-responsive circuits adapt during the development of diet-induced obesity (Lindqvist et al 2005;Briggs et al 2010), and whether GHS-R1A antagonists could provide an effective therapy for this disease area.…”