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The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

Dual GIP and GLP-1 receptor agonist Tirzepatide improves Beta-cell function and insulin sensitivity in type 2 diabetes. Keywords: metabolic hormones; pharmacotherapy; systemic metabolism; tirzepatide; type 2 diabetes EN metabolic hormones pharmacotherapy systemic metabolism tirzepatide type 2 diabetes 1222 1223 2 02/16/23 20230301 NES 230301 Seetharaman et al. showed that innovations in pharmacotherapy to ameliorate the symptoms associated with type 2 diabetes promote more insightful developments in medicine. [Extracted from the article]