SLC37A2, Macrophage Inflammation and Metabolic Diseases

Obesity is one of the most prevalent diseases globally, leading to insulin resistance, type 2 diabetes (T2D) and atherosclerosis, all of which are driven by obesity-associated chronic inflammation. A hallmark of obesity-associated inflammation is a switch from alternative-activated (M2) to classically activated pro-inflammatory (M1) macrophages in adipose tissue, with enhanced local and systemic inflammation and impaired immune function. M1 macrophages require glucose as an energy source, but alternative-activated (M2) macrophages switch to fatty acid oxidation for energy needs. However, the mechanism by which cellular glucose transporters contribute to glucose and fatty acid metabolic reprogramming is largely unknown.

Solute carrier (SLC)37A2, belonging to the SLC37 family, is a phosphate-linked glucose-6-phosphate (G6P) transporter, anchored in the endoplasmic reticulum (ER) membrane. SLC37A2 is highly expressed in macrophages and neutrophils relative to other SLC37 family members. Our preliminary data suggest that macrophage SLC37A2 is acutely downregulated during classical activation and upregulated during alternative activation. Suppression of SLC37A2 is sufficient to promote M1 and attenuate M2 polarization of mouse macrophages. Conversely, constitutive overexpression of SLC37A2 blunts M1 polarization in response to Toll-like receptor (TLR) agonists.

Goals of the study

To investigate SLC37A2-mediated glucose-dependent metabolic programming and to determine how it impacts macrophage inflammation and inflammation-related metabolic diseases.

  • Specific Aim 1: We will determine whether SLC37A2 regulates macrophage glucose homeostasis and M1/M2 polarization.
  • Specific Aim 2: We will determine whether SLC37A2 affects obesity and insulin resistance by reprogramming macrophage M1/M2 polarization.
  • Specific Aim 3: We will determine whether SLC37A2 affects atherogenesis by reprogramming macrophage M1/M2 polarization.

The proposed studies will demonstrate whether SLC37A2 regulates macrophage glucose metabolism and reprograms macrophage M1/M2 polarization. This project will provide novel information regarding the role of glucose metabolism in macrophage phenotypic switching, potentially leading to novel therapeutic strategies for chronic inflammatory diseases driven by M1-skewed proinflammatory macrophages.