Linking Inflammation and Metabolism

Abstract

Food is good for you--but only up to a point. In fact, the complications of excess nutrients and consequent obesity represent major factors influencing human health. Obesity, metabolic diseases like diabetes, and exposure to excess nutrients are all associated with inflammatory responses. Wellen et al . suspected that there might be natural regulatory factors that limit inflammation during fluctuations in nutrient load. They therefore conducted gene expression screens and identified STAMP2 [six-transmembrane protein of prostate 2, also known as TNF-induced adipose-related protein (TIARP) or six-transmembrane epithelial antigen of prostate 4 (STEAP)] as a protein whose mRNA was decreased in adipose tissue of obese animals lacking proinflammatory signaling by tumor necrosis factor-α (TNFα). Expression of STAMP2 mRNA and protein in adipose tissue was increased after feeding of normal, but not obese, mice. When expression of STAMP2 was decreased with RNAi in cultured 3T3-L1 adipocytes, the cells showed an increased inflammatory response (cytokine production) in response to excess glucose or stimulation with TNFα, which correlated with impaired responses of the cells to insulin. In STAMP2 –/– mice, the authors observed increased inflammatory responses when they intraperitoneally administered glucose and lipid. Even when fed on a normal diet, the STAMP2 –/– mice showed changes in body weight, glucose metabolism, and lipid metabolism characteristic of metabolic disease, including fat accumulation, glucose intolerance, and insulin resistance. The molecular mechanisms by which STAMP2 functions remain to be determined. The protein has metalloreductase activity and appears to function in cellular uptake of iron and copper. Whatever its mechanism of action, the authors argue that STAMP2 appears to have a central role in coordination of nutrient balance and metabolism with inflammatory responses. K. E. Wellen, R. Fucho, M. F. Gregor, M. Furuhashi, C. Morgan, T. Lindstad, E. Vaillancourt, C. Z. Gorgun, F. Saatcioglu, G. S. Hotamisligil, Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 129 , 537-548 (2007). [Online Journal]