Chronic inflammation of white adipose tissue is a key link between obesity and the associated metabolic syndrome. Transient receptor potential melastatin-like 7 (TRPM7) is known to be related to inflammation; however, the role of TRPM7 in adipocyte phenotype and function in obesity remains unclear. Here, we observe that the activation of adipocyte TRPM7 plays an essential role in pro-inflammatory responses. Adult male mice are used in our experiments. Adipocyte-specific deficiency in TRPM7 attenuates the pro-inflammatory phenotype, improves glucose homeostasis, and suppresses weight gain in mice fed a high-fat diet. Mechanistically, the pro-inflammatory effect of TRPM7 is dependent on Ca signaling. Ca influx initiated by TRPM7 enhances transforming growth factor-β activated kinase 1 activation via the co-regulation of calcium/calmodulin-dependent protein kinase II and tumor necrosis factor receptor-associated factor 6, leading to exacerbated nuclear factor kappa B signaling. Additionally, obese mice treated with TRPM7 inhibitor are protected against obesity and insulin resistance. Our results demonstrate TRPM7 as a factor in the development of adipose inflammation that regulates insulin sensitivity in obesity.