Helmholtz Diabetes Center Institute for Diabetes and Obesity (IDO)

April 2024 Nature Metabolism

Felix Klingelhuber, Scott Frendo-Cumbo, Muhmmad Omar-Hmeadi, Lucas Massier, Pamela Kakimoto, Austin J. Taylor, Morgane Couchet, Sara Ribicic, Martin Wabitsch, Ana C. Messias, Arcangela Iuso, Timo D. Müller, Mikael Rydén, Niklas Mejhert & Natalie Krahmer

A spatiotemporal proteomic map of human adipogenesis

White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.

February 2024 Nature Metabolism

Grandl G, Collden G, Feng J, Bhattacharya S, Klingelhuber F, Schomann L, Bilekova S, Ansarullah, Xu W, Far FF, Tost M, Gruber T, Bastidas-Ponce A, Zhang Q, Novikoff A, Liskiewicz A, Liskiewicz D, Garcia-Caceres C, Feuchtinger A, Tschöp MH, Krahmer N, Lickert H, Müller TD.

Global, neuronal or β cell-specific deletion of inceptor improves glucose homeostasis in male mice with diet-induced obesity

Insulin resistance is an early complication of diet-induced obesity (DIO)1, potentially leading to hyperglycaemia and hyperinsulinaemia, accompanied by adaptive β cell hypertrophy and development of type 2 diabetes2. Insulin not only signals via the insulin receptor (INSR), but also promotes β cell survival, growth and function via the insulin-like growth factor 1 receptor (IGF1R)3,4,5,6. We recently identified the insulin inhibitory receptor (inceptor) as the key mediator of IGF1R and INSR desensitization7. But, although β cell-specific loss of inceptor improves β cell function in lean mice7, it warrants clarification whether inceptor signal inhibition also improves glycaemia under conditions of obesity. We assessed the glucometabolic effects of targeted inceptor deletion in either the brain or the pancreatic β cells under conditions of DIO in male mice. In the present study, we show that global and neuronal deletion of inceptor, as well as its adult-onset deletion in the β cells, improves glucose homeostasis by enhancing β cell health and function. Moreover, we demonstrate that inceptor-mediated improvement in glucose control does not depend on inceptor function in agouti-related protein-expressing or pro-opiomelanocortin neurons. Our data demonstrate that inceptor inhibition improves glucose homeostasis in mice with DIO, hence corroborating that inceptor is a crucial regulator of INSR and IGF1R signalling.

Dezember 2023 Nature Metabolism

Liskiewicz A, Khalil A, Liskiewicz D, Novikoff A, Grandl G, Maity-Kumar G, Gutgesell RM, Bakhti M, Bastidas-Ponce A, Czarnecki O, Makris K, Lickert H, Feuchtinger A, Tost M, Coupland C, Ständer L, Akindehin S, Prakash S, Abrar F, Castelino RL, He Y, Knerr PJ, Yang B, Hogendorf WFJ, Zhang S, Hofmann SM, Finan B, DiMarchi RD, Tschöp MH, Douros JD, Müller TD.

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR–GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1,2,3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6,7,8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR–GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR–GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.