Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in nutrient homeostasis. GIP receptor (GIPR) is constitutively internalized and returned to the plasma membrane, atypical behavior for a G protein-coupled receptor (GPCR). GIP promotes GIPR downregulation from the plasma membrane by inhibiting recycling without affecting internalization. This transient desensitization is achieved by altered intracellular trafficking of activated GIPR. GIP stimulation induces a switch in GIPR recycling from a rapid endosomal to a slow TGN pathway. GPCR kinases and β-arrestin2 are required for this switch in recycling. A coding sequence variant of GIPR, which has been associated with metabolic alterations, has altered post-activation trafficking characterized by enhanced downregulation and prolonged desensitization. Downregulation of the variant requires β-arrestin2 targeting to the TGN but is independent of GPCR kinases. The single amino acid substitution in the variant biases the receptor to promote GIP stimulated β-arrestin2 recruitment without receptor phosphorylation, thereby enhancing downregulation.

Objective Recent studies indicate that brown adipose tissue, in addition to its role in thermogenesis, has a role in the regulation of whole-body metabolism. Here we characterize the metabolic effects of deleting Rab10, a protein key for insulin stimulation of glucose uptake into white adipocytes, solely from brown adipocytes. Methods We used a murine brown adipocyte cell line and stromal vascular fraction-derived in vitro differentiated brown adipocytes to study the role of Rab10 in insulin-stimulated GLUT4 translocation to the plasma membrane and insulin-stimulated glucose uptake. We generated a brown adipocyte-specific Rab10 knockout for in vivo studies of metabolism and thermoregulation. Results We demonstrate that deletion of Rab10 from brown adipocytes results in a two-fold reduction of insulin-stimulated glucose transport by reducing translocation of the GLUT4 glucose transporter to the plasma membrane, an effect linked to whole-body glucose intolerance and insulin resistance in female mice. This effect on metabolism is independent of the thermogenic function of brown adipocytes, thereby revealing a metabolism-specific role for brown adipocytes in female mice. The reduced glucose uptake induced by Rab10 deletion disrupts ChREBP regulation of de novo lipogenesis (DNL) genes, providing a potential link between DNL in brown adipocytes and whole-body metabolic regulation in female mice. However, deletion of Rab10 from male mice does not induce systemic insulin resistance, although ChREBP regulation is disrupted. Conclusions Our studies of Rab10 reveal the role of insulin-regulated glucose transport into brown adipocytes in whole-body metabolic homeostasis of female mice. Importantly, the contribution of brown adipocytes to whole-body metabolic regulation is independent of its role in thermogenesis. It is unclear whether the whole-body metabolic sexual dimorphism is because female mice are permissive to the effects of Rab10 deletion from brown adipocytes or because male mice are resistant to the effect.

SummaryThe role of brown adipose tissue (BAT) in thermogenesis is widely appreciated, whereas its more recently described role in whole-body metabolism is not as well understood. Here we demonstrate that deletion of Rab10 from brown adipocytes reduces insulin-stimulated glucose transport by inhibiting translocation of the GLUT4 glucose transporter to the plasma membrane. This blunting of glucose uptake into brown adipocytes induces glucose intolerance and insulin-resistance in female but not male mice. The defect in glucose uptake does not affect the thermogenic function of BAT, and the dysregulation of whole-body metabolism is independent of the thermogenic function of BAT, thereby revealing a metabolism-specific role for BAT in female mice. The reduced glucose uptake induced by RAB10 deletion disrupts ChREBP regulation of the expression of de novo lipogenesis-related (DNL) genes, providing a link between DNL in BAT and whole-body metabolic regulation that is independent of thermogenesis.

Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, has a role in controlling postprandial metabolic tone. A GIP receptor (GIPR) variant (Q354, rs1800437) is associated with enhanced glucose tolerance and a lower BMI. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant. Islets isolated from both male and female GIPR-Q variant mice have an enhanced glucose sensitivity and enhanced GIP response. In whole animal studies only female GIPR-Q variant mice are more glucose tolerant, whereas males have normal glucose tolerance but an enhanced sensitivity to GIP. In both sexes postprandial GIP levels are reduced, revealing feedback between the sensitivity of GIP target tissues and the secretion of GIP from intestinal endocrine cells. In line with the association of the variant with reduced BMI, GIPR-Q350 mice are resistant to dietinduced obesity. GIPR, a GPCR, is coupled to elevated cAMP. Prior studies have established altered post-activation traffic of the GIPR-Q variant without a change in affinity for GIP or in cAMP production. Consequently, our data link altered intracellular traffic of the GIPR-Q variant with GIP metabolic control of metabolism. Incretin hormone action is targeted in treatment of insulin-resistance, and our findings support pharmacologic targeting the GIPR to mimic the altered trafficking of the GIPR-Q variant as a potential strategy to enhance GIP metabolic effects in treatment of insulin resistance.