Fat cell signaling molecules identified as critical for regulating metabolic health in mice
Researchers have identified new ways that adipocyte (fat cell) signaling can disrupt glucose (sugar) regulation in mice, with metabolic consequences throughout the body. Adipocytes are known to mediate obesity-related disruptions in glucose metabolism, and knowing how these cells “talk” with other cells and organs in the body could lead to new targets for diabetes treatments. One major group of signaling molecules in animals is the “G proteins,” which transmit crucial information about a cell’s environment to its interior and thus inform the cell’s behavior. Some G proteins help to regulate adipocyte function and blood glucose levels, but the specific role of the Gi family proteins in adipocytes was unclear.
To determine Gi proteins’ function in fat cells, researchers created a mouse model that lacks functional Gi proteins in adipocytes. Compared to normal male mice, male mice lacking Gi proteins in their adipocytes displayed many signs of poor metabolic health. The lack of Gi proteins in their adipocytes impaired the mice’s ability to regulate their blood glucose levels. The mice also showed signs of reduced insulin sensitivity in various organs, including the liver and muscle, particularly when given a high-fat diet. Scientists found that mice on a high-fat diet that lacked Gi proteins in their adipocytes had increased fatty acid concentrations in the blood, increased fat in the liver, increased markers of inflammation in fat tissue and blood, and impaired insulin receptor signaling compared to normal mice on the same diet. The researchers then demonstrated that functional Gi proteins in adipocytes were required to prevent these poor health outcomes and to maintain metabolic health. Furthermore, work with a different mouse model showed that selectively activating Gi signaling in adipocytes improved both glucose metabolism and insulin sensitivity regardless of diet. Enhancing Gi protein signaling for longer periods of time also helped improve various aspects of metabolic health while on a high-fat diet.
Though these findings will need to be confirmed in humans, they suggest that the Gi family of proteins in adipocytes is critical to maintaining healthy glucose regulation in mice and is particularly important when the mice are given a high-fat diet. Selectively activating these proteins may also be a novel way to combat the symptoms of metabolic disorders, such as diabetes, in humans.
Wang L, Pydi SP, Zhu L,…Wess J. Adipocyte Gi signaling is essential for maintaining whole-body glucose homeostasis and insulin sensitivity. Nat Commun 11: 2995, 2020.