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

Previous studies identify a role for hypothalamic glia in energy balance regulation; however, a narrow hypothalamic focus provides an incomplete understanding of how glia throughout the brain respond to and regulate energy homeostasis. We examined the responses of glia in the dorsal vagal complex (DVC) to the adipokine leptin and high fat diet-induced obesity. DVC astrocytes functionally express the leptin receptor; in vivo pharmacological studies suggest that DVC astrocytes partly mediate the anorectic effects of leptin in lean but not diet-induced obese rats. Ex vivo calcium imaging indicated that these changes were related to a lower proportion of leptin-responsive cells in the DVC of obese versus lean animals. Finally, we investigated DVC microglia and astroglia responses to leptin and energy balance dysregulation in vivo: obesity decreased DVC astrogliosis, whereas the absence of leptin signaling in Zucker rats was associated with extensive astrogliosis in the DVC and decreased hypothalamic micro-and astrogliosis. These data uncover a novel functional heterogeneity of astrocytes in different brain nuclei of relevance to leptin signaling and energy balance regulation.

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.

Introduced less than two decades ago, glucagon‐like peptide‐1 receptor agonists rapidly reshaped the field of Type 2 diabetes mellitus (T2DM) care by providing glycaemic control in tandem with weight loss. However, FDA‐approved GLP‐1 receptor agonists are often accompanied by nausea and emesis and, in some lean T2DM patients, by undesired anorexia. Importantly, the hypophagic and emetic effects of GLP‐1 receptor agonists are caused by activation of central GLP‐1 receptors. This review summarizes two different approaches to mitigate the incidence and severity of nausea and emesis related to GLP‐1 receptor agonists: conjugation with vitamin B12, or related corrin ring‐containing compounds (‘corrination’), and development of dual agonists of GLP‐1 receptors with glucose‐dependent insulinotropic polypeptide (GIP). Such approaches could lead to the generation of GLP‐1 receptor agonists with improved therapeutic efficacy, thus decreasing treatment attrition, increasing patient compliance and extending treatment to a broader population of T2DM patients. The data reviewed show that it is possible to pharmacologically separate the emetic effects of GLP‐1 receptor agonists from their glucoregulatory action. LINKED ARTICLES This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc

Video-assisted hot stage polarized light microscopy of 55 quasienantiomeric pairs, constructed from 22 chiral diarylamides that systematically differ in topology, reveals the structural boundaries of molecular shape to supramolecular assembly.