Inflammation and obesity: STAMPing out insulin resistance?

Abstract

A new study identifies STAMP2 (six-transmembrane protein of prostate 2) as a potential molecular link between obesity, inflammation and insulin resistance. Obesity-induced insulin resistance, type II diabetes and associated metabolic syndromes, whose prevalence continues to grow despite having already reached epidemic proportions, are now felt to be linked to a state of chronic, subacute inflammation. Adipose tissue is a primary site for initiating the inflammation, although other metabolically active tissues are also involved and contribute to pathogenesis. Despite major advances that are helping to unravel the biochemical and cellular changes associated with obesity, the initiating events that link obesity to the inflammatory state are poorly understood. Identifying these early initiating events is nevertheless crucial to understanding the pathogenesis of insulin resistance and type II diabetes and to the potential development of new methods for intervention. Until recently, adipose tissue was viewed as an inert reservoir for energy storage. However, now we know that it is a complex metabolic and endocrine organ capable of expressing and secreting bioactive proteins and mediators involved in a broad range of biological processes. The increasing list of bioactive, adipose-derived mediators includes a broad range of cytokines and chemokines and other regulatory molecules (for example, leptin, TNF-α, IL-6, SAA-1, MCP-1, resistin, PAI-1, RBP4, and so on) that have potential roles in both innate immunity and metabolism. Gökhan Hotamisligil's group helped establish early links between metabolic disease and inflammatory processes,1,2,3 and now they have identified the STAMP2 to be a new player at the interface between inflammation and metabolism in adipocytes4 (see Figure 1). Given the potential for adipocytes to initiate inflammatory responses, the authors of the new study hypothesized that counter-regulatory mechanisms might dampen inflammation and so protect these cells. To identify such proteins, they chose to screen for genes differentially regulated in obese mice either by TNF-α signaling or PPARγ agonists (thiazolidinediones, or TZDs). STAMP2, a protein abundantly expressed in adipose tissue, was reduced in ob/ob mice either deficient in TNF-α signaling or treated with a TZD. STAMP2 expression is differentiation-dependent and controlled by the adipogenic transcription factor, CEBPα, but not PPARγ. So it seemed that TZD reduction of STAMP2 expression in ob/ob mice occurred through an alternative mechanism. The next challenge was to test their hypothesis that STAMP2 is a potential counter-regulator of the pathological processes that lead to insulin resistance and metabolic disease. The authors built their case on a series of experiments. First they showed that nutritional regulation of STAMP2 expression in both cultured adipocytes and lean adipose tissue is lost in ob/ob and diet-induced obesity models. Their in vitro gain-of-function studies showed that STAMP2 improves insulin sensitivity. By contrast, the loss of STAMP2 function, either in vitro (RNAi-treated 3T3-L1 adipocytes) or in vivo (STAMP2−/− mice), elevated inflammatory markers, diminished insulin action and sensitivity, and hindered glucose uptake. Macrophage numbers increased in STAMP2-deficient adipose tissue compared to wild type controls, a finding that is consistent with previous studies that correlate macrophage infiltration with inflammation and insulin resistance. Since oxidative stress can cause metabolic dysfunction and induce inflammation, the authors also examined antioxidant gene expression in STAMP2-deficient adipose tissue and found reductions in catalase, glutathione-S-transferase (GST) and superoxide dismutase 1 (SOD1), and upregulation of NADPH oxidase 1. This pattern of gene expression is similar to patterns previously observed in obesity, and suggests that adipose tissue may be more susceptible to oxidative stress in the absence of STAMP2. Nonetheless, it is still unclear whether the observed changes in gene expression in adipose tissue are attributable to adipocytes or to other cell types present in adipose tissue such as macrophages. While the authors focused primarily on the effects of STAMP2 deficiency in adipose tissue, they also tested for broader consequences. STAMP2-null mice exhibited hyperlipidemia and they weighed more and had lower metabolic rates. Hyperinsulinemic–euglycemic clamp studies revealed impairments in hepatic insulin signaling and the ability of insulin to suppress hepatic glucose production. Glucose disposal, which occurs primarily in muscle, was also impaired. These findings suggest one of two things: either alterations in the adipose tissue of STAMP2-null mice have systemic effects or STAMP2 deletion affects each tissue, particularly in liver, more or less independently. This important distinction has not yet been made. Since nutrient oversupply itself can be pro-inflammatory, and in adipocytes STAMP