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Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic beta cells in response to feeding. We recently reported that amylin potently reduces food intake, body weight, and adiposity when delivered into the 3rd cerebral ventricle (i3vt) of rats. We have now infused i3vt a specific antagonist (AC187) to ascertain the physiological relevance of central amylin in the control of energy balance. After establishing the ability of i3vt AC187 to block the anorexic effect of i3vt amylin, we performed an experiment to examine the impact of acute inhibition of central amylin signaling on feeding. Separate groups (n = 7/group) of ad lib-fed male Long Evans rats were given one bolus i3vt infusion of synthetic cerebrospinal fluid vehicle (CSF) or AC187 (250 or 1000 pmol). Acute infusion of AC187 tended to increase 1-h food intake and significantly elevated 4-h intake. Both the 250 and 1000 pmol doses produced significant increases as compared to CSF. In another experiment designed to tonically inhibit central amylin signaling over an extended period, two other groups of rats (n = 6/group) received continuous i3vt infusion of CSF or 100 pmol/h AC187 over 14 days via implantable osmotic pumps. Rats receiving AC187 ate significantly more food over the 14-day infusion period relative to controls (CSF = 322 +/- 6 g, AC187 = 360 +/- 12 g). Although body weight was not significantly affected, body fat was increased by about 30% in the AC187 rats, with no difference in lean tissue between the groups. Additionally, although fasting plasma glucose did not differ between the CSF and AC187 groups after 14 days of infusion, plasma insulin was significantly elevated in the AC187 rats. In summary, the present results document significant increases of food intake and body adiposity resulting from inhibition of central amylin signaling. They are consistent with our hypothesis that CNS actions of endogenous amylin contribute to the long-term regulation of energy balance.

Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms.