Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms

Abstract

Aims: To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate.Materials/Methods: Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK).A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.Results: Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.M. Ghidewon and H.S. Wald contributed equally in their roles as first author T. Borner and H. J. Grill contributed equally to this in their roles as senior author.

Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity

“…These data suggest that GLP-1 and GDF-15 act through distinct pathways. Interestingly, Ghidewon et al showed that dual treatment with GDF-15 and GLP-1 induces more robust weight loss in mice compared to each agent alone, proposing potential synergistic effects [31].…”

“…Although we show that liraglutied and lorcaserin weight loss pathways are independent of GDF-15, it still remains to be fully elucidated if GDF-15 does play a role in weight regulation through other pathways. Based on studies in mice, if GDF-15 can cause appetite suppression, that could be through a) activating the GFRAL receptor located in the hindbrain [34], b) gastrointestinal malaise induction [14,31,[35][36][37][38], and/or c) efferent vagal signaling causing delayed gastric emptying [12]. As GDF-15 may act through multiple mechanisms, its combination with different weight loss pharmacological agents could potentiate their effects, as proposed by data in animal studies [31].…”

“…Based on studies in mice, if GDF-15 can cause appetite suppression, that could be through a) activating the GFRAL receptor located in the hindbrain [34], b) gastrointestinal malaise induction [14,31,[35][36][37][38], and/or c) efferent vagal signaling causing delayed gastric emptying [12]. As GDF-15 may act through multiple mechanisms, its combination with different weight loss pharmacological agents could potentiate their effects, as proposed by data in animal studies [31]. Thus, the GDF-15 effects need to be further studied in humans.…”

Research Progress on the Role and Mechanism of GDF15 in Body Weight Regulation

“…However, GDF15 was used in combination with stimulating the release of satiety signals in the gastrointestinal tract of rats. It was found that the combined use of the two did not have a synergistic effect on reducing food intake [58], suggesting that GDF15 did not reduce food intake by increasing satiety.…”

Creation of a Peptide Antagonist of the GFRAL–RET Receptor Complex for the Treatment of GDF15-Induced Malaise

“…Growth differentiation factor 15 (GDF15) is a stress-response cytokine expressed by a variety of tissues that is secreted into circulation in response to a wide array of stimuli and chronic diseases, including cancer and chemotherapy. − GDF15 signaling gained significant attention after it was confirmed to be an agonist at the GDNF family receptor α-like (GFRAL)-RET complex. − Previously published reports highlighted the promise of GDF15-mediated signaling via GFRAL as a potential target for the pharmacologic treatment of obesity because of its potent capacity to suppress food intake. ,, Expression of GFRAL-RET in the central nervous system (CNS) is limited to neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) − of the brainstem, where it provides critical contributions to energy balance and the induction of nausea and emesis. , Importantly, these two adjacent structures do not possess a functional blood–brain barrier, allowing circulating GDF15 and other agents (including systemically delivered substances) to directly reach the neurons located in the AP/NTS. , Results from several recent reports revealed that the anorectic response to GDF15 signaling was largely secondary to malaise, − and as such the GDF15-GFRAL signaling pathway may be a potential target for the development of new antiemetic pharmacological agents. Most recently, Hsu et al reported that GFRAL knockout mice were insensitive to the long-term anorexia and cachexia/weight loss that typically results from the administration of cisplatin.…”