Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6

Abstract

Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from β-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1β (IL-1β) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1β in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1)] were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation.is an incretin hormone secreted from intestinal endocrine L-cells and also from pancreatic α-cells. Its ability to stimulate insulin secretion and regulate blood glucose has been used as a treatment for type 2 diabetes. Importantly, GLP-1 and its long-lasting analogs reduce food intake and body weight (see ref. 1 for review). These effects have been regarded as of potential clinical relevance for successful treatment of obesity. There is limited knowledge regarding the mechanisms behind the anorexic effect of GLP-1, but it is likely exerted at the level of the CNS (2-4). Central GLP-1 receptors (GLP-1R) are distributed throughout the CNS energybalance-regulating areas, including the hypothalamus and hindbrain (5). GLP-1-producing neurons in the nucleus of the solitary tract are likely the main source of the endogenous ligand to the central GLP-1Rs (6, 7). Peripherally applied long-lasting analogs, due to their ability to cross the blood brain barrier (8, 9), can also engage the central GLP-1R populations, making these CNS receptors a relevant clinical target. Even though the contribution of the central GLP-1Rs to energy balance regulation is clear, the understanding of the neural pathways and mechanisms...

Myokines in insulin resistance and type 2 diabetes

“…Furthermore, an interaction between GLP-1 and IL-6 in the brain has been recently described, showing that activation of central GLP-1 receptors increases IL-6 expression in the hypothalamus and hindbrain. These data point towards a role of central IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation [55].…”

Brain IL-6—Where Amylin and GLP-1 Antiobesity Signaling Congregate

“…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.…”

“…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.…”

“…They both decrease food intake and body weight via effects on the brain, and GLP-1 also acts via the vagus nerve. Recent evidence indicates that increased production of IL-6 in the hypothalamus can mediate decreases in food intake and body weight as well as increased leptin sensitivity in response to amylin and GLP-1 (3,8,19). Earlier data indicate that brain IL-6 by itself can decrease body fat mass (13,14).…”

Hypothalamic Alterations in Obesity

“…In addition, acute icv-but not peripheral-injection of IL-6 in rats increased energy expenditure, suggesting that the antiobesity effects of IL-6 are exerted mainly through its actions on the CNS [83]. A recent study has shown that central injection of a GLP1 receptor agonist with well-known weight-lowering effects potently increased hypothalamic expression of IL-6 [85]. IL-6 can also be produced and released by skeletal muscle, and mediate the effects of exercise on metabolism [86].…”