A prerequisite for the homeostatic control of fat mass is the existence of peripheral hormones that, together with nervous afferents, signal the state of energy balance to adipostatic circuits in the brain. It is assumed that the effects of these signals are mediated, at least in part, by changes in key neurotransmitters, especially those located in the hypothalamus. It has been known for many years that leptin from adipose tissue engages neurons producing α-melanocyte–stimulating hormones, while ghrelin from the empty stomach stimulates neurons producing neuropeptide Y/agouti-related peptide/γ-aminobutyric acid. These two neuronal populations in the arcuate nucleus mediate these two counterregulatory canonical signals for energy homeostasis (1). In addition, peripheral energy balance–reporting hormones may act on the brain stem (2).
In this issue of Diabetes, Le Foll et al. (3) report that the pancreatic hormone amylin may use interleukin-6 (IL-6) as a noncanonical signal mediator in the brain. Thus, amylin may be dependent upon expression of IL-6 in the hypothalamus to exert its effects to reduce body weight and to increase leptin sensitivity.
Like leptin and ghrelin, amylin is a periphery-to-brain messenger of importance for energy balance. Proamylin is coreleased with insulin from the β-cells after meals, and amylin decreases blood glucose (4,5). Amylin reduces food intake and body weight and potentiates effects of leptin (4–6). The amylin analog pramlintide, which is used clinically for the treatment of diabetes, has been shown to decrease body weight by more than 2 kg in humans (7), but the underlying mechanisms have remained unclear.
Recently published results indicate that IL-6 could be a central nervous system (CNS) mediator for the body weight– and food intake–reducing effects of another peripheral messenger of energy balance besides amylin: glucagon-like peptide 1 (GLP-1) (8). There are several similarities between GLP-1 and amylin. 1) They are both derived from the abdomen after meals and 2) target the brain to cause a modest but undeniable decrease in food intake and body weight, and a GLP-1 analog is now used clinically for obesity (9). 3) In high doses and early during treatment, both can induce nausea. 4) Both peptides improve glucose homeostasis and are used to treat diabetes. 5) Both decrease gastric emptying and decrease glucagon secretion, effects that could contribute to improved glucose metabolism (4,5,9). 6) In the brain, both act on the area postrema in the brain stem, but they may also act on the hypothalamus (4,5,9). However, there also differences. GLP-1 is an incretin from the gut that acts largely by increasing insulin secretion, while amylin is cosecreted with insulin and seems to potentiate the effects of insulin (4,5,9) (Fig. 1). Unlike amylin, GLP-1 is also produced by a specific neuronal population in the brain, the nucleus of the solitary tract neurons in the brain stem. Unlike amylin, GLP-1 partly acts via the vagus nerve or is at least dependent on the vagus for its effects (4,10) (Fig. 1).
The results of the study by Le Foll et al. (3) showing that amylin acts via the cytokine IL-6 to decrease body weight and to increase leptin sensitivity and the previous results indicating that IL-6 could mediate the anorectic and antiobesity effect of GLP-1 (8) may seem surprising. IL-6 is a cytokine best known for its effects on the immune defense (11). It has also been implicated in cachexia in connection with infections and cancer (12). However, there are indications that IL-6 in the CNS also plays a role to suppress body fat in healthy individuals. Mature-onset obesity has been observed in IL-6 knockout mice fed a low-fat diet, and this effect appears to be exerted at the level of the CNS (13,14). Transgenic mice overexpressing IL-6 in the brain and rodents receiving brain delivery of IL-6 become obesity resistant (15–17). Finally, CNS blockade of IL-6 can inhibit the beneficial effects of exercise on insulin and leptin sensitivity (18). In conclusion, there are several reports indicating that IL-6 decreases obesity via effects in the brain, results that are in line with a mediating role for IL-6 in the antiobesity effects of amylin and GLP-1.
The idea that GLP-1 acts via increased IL-6 at the CNS level (8,19) also gains support from a seminal report by Donath and colleagues (20) that GLP-1 is released from L cells in the gut in response to IL-6, and that this mediates metabolically beneficial effects of IL-6. Thus, IL-6 and GLP-1 seem to interact at several sites in the body, and these interactions, in general, appear to promote metabolic health. There are few reports about possible interactions between IL-6 and amylin outside of the CNS.
It is concluded that amylin and GLP-1 may act to decrease body weight via increased production of IL-6 in different parts of the brain. Amylin and GLP-1 have several other features in common, as they are both secreted during meals, both promote the storage of food nutrients to improve glucose metabolism, and both decrease body weight. Not surprisingly, both amylin and GLP-1 analogs are used pharmacologically to treat diabetes and, in the case of GLP-1, to treat obesity per se. Given the clinical importance of amylin and GLP-1, it is crucial to understand the mechanisms of action of these peptides. Recent evidence suggests that amylin and GLP-1 engage noncanonical signals in the hypothalamus, in the form of IL-6 rather than neuropeptide Y/agouti-related peptide and α-melanocyte–stimulating hormone, for the regulation of food intake, body fat mass, and body weight.
See accompanying article, p. 1621.
Acknowledgments. The authors thank Dr. Erik Schéle for his skilled assistance with illustrations.
Funding. This work was supported by grants from the Swedish Research Councilhttp://dx.doi.org/10.13039/501100001862 (K2013–54X-09894–19-3) and by European Commission FP7 funding (grant agreement 245009, Full4Health FP7-KBBE-2010–4-266408).
Duality of Interest. No potential conflicts of interest relevant to this article were reported.