Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding

Highlights d The Cbi-Ex4 conjugate retains GLP-1R agonism in vitro and improved half-life in vivo d Cbi-Ex4 displays similar glucoregulatory properties compared to native Ex4 d Cbi-Ex4 does not induces anorexia, weight loss, or hindbrain neuronal activation d In contrast to Ex4, Cbi-Ex4 does not cause emesis indicative of improved tolerance

Aim To develop a conjugate of vitamin B12 bound to the glucagon‐like peptide‐1 receptor (GLP‐1R) agonist exendin‐4 (Ex4) that shows reduced penetrance into the central nervous system while maintaining peripheral glucoregulatory function. Methods We evaluated whether a vitamin B12 conjugate of Ex4 (B12‐Ex4) improves glucose tolerance without inducing anorexia in Goto‐Kakizaki (GK) rats, a lean type 2 diabetes model of an understudied but medically compromised population of patients requiring the glucoregulatory effects of GLP‐1R agonists without anorexia. We also utilized the musk shrew (Suncus murinus), a mammalian model capable of emesis, to test B12‐Ex4 on glycaemic profile, feeding and emesis. Results In both models, native Ex4 and B12‐Ex4 equivalently blunted the rise in blood glucose levels during a glucose tolerance test. In both GK rats and shrews, acute Ex4 administration decreased food intake, leading to weight loss; by contrast, equimolar administration of B12‐Ex4 had no effect on feeding and body weight. There was a near absence of emesis in shrews given systemic B12‐Ex4, in contrast to reliable emesis produced by Ex4. When administered centrally, both B12‐Ex4 and Ex4 induced similar potency of emesis, suggesting that brain penetrance of B12‐Ex4 is required for induction of emesis. Conclusions These findings highlight the potential therapeutic value of B12‐Ex4 as a novel treatment for type 2 diabetes devoid of weight loss and with reduced adverse effects and better tolerance, but similar glucoregulation to current GLP‐1R agonists.

Background/objectives The murine postnatal leptin surge occurs within the first 4 weeks of life and is critical for neuronal projection development within hypothalamic feeding circuits. Here we describe the influence of nutritional status on the timing and magnitude of the postnatal leptin surge in mice. Methods Plasma leptin concentrations were measured 1–3 times per week for the first 4 weeks of life in C57BL/6J pups reared in litters adjusted to 3 (small), 7–8 (normal), or 11–12 (large) pups per dam fed breeder chow or raised in litters of 7–8 by dams fed high-fat diet (HFD) ad libitum starting either prior to conception or at parturition. Results Mice raised in small litters become fatter than pups raised in either normal or large litters. The leptin surge in small litter pups starts earlier, lasts longer, and is dramatically larger in magnitude compared to normal litter pups, even when leptin concentrations are normalized to fat mass. In mice reared in large litters, weight gain is diminished and the surge is both significantly delayed and lower in magnitude compared to control pups. Pups reared by HFD-fed dams (starting preconception or at parturition) are fatter and have augmented leptin surge magnitude compared to pups suckled by chow-fed dams. Surge timing varies depending upon nutritional status of the pup; the source of the surge is primarily subcutaneous adipose tissue. At peak leptin surge, within each group, fat mass and plasma leptin are uncorrelated; in comparison with adults, pups overproduce leptin relative to fat mass. Plasma leptin elevation persists longer than previously described; at postnatal day 27 mice continue overproducing leptin relative to fat mass. Conclusions In mice, small litter size and maternal HFD feeding during the perinatal period augment the plasma leptin surge whereas large litter size is associated with a delayed surge of reduced magnitude.

A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.