Glucose homeostasis relies on continuous crosstalk between several organs: pancreatic beta cells secrete insulin in response to glucose, and insulin in turn acts on its target tissues—particularly the liver, muscle, and adipose tissue—to bring blood glucose back within a physiological range. Beyond glucose alone, beta cells in fact integrate a multitude of metabolic and endocrine signals—lipids, hormones, cytokines—that reflect the metabolic state of the organism. In type 2 diabetes, this coordination becomes dysregulated, leading to inadequate insulin secretion and glucose intolerance. White adipose tissue plays a central role in this imbalance: as a bona fide endocrine organ, it can, in obesity, secrete deleterious factors that impair the function of other tissues, including beta cells. The critical regulatory components of this adipocyte reprogramming, however, remained poorly identified.
The authors focused on GPS2 (G protein pathway suppressor 2), a transcriptional coregulator and subunit of a chromatin-modifying corepressor complex, which previous work had already suggested influences adipocyte functions in obesity and type 2 diabetes. In humans, the expression level of GPS2 messenger RNA in white adipose tissue was found to correlate with the rate of insulin secretion. To establish the causality of this association, the team used mice with adipocyte-specific GPS2 knockout, generated by crossing "floxed" Gps2 mice with mice expressing Cre recombinase under the control of the adiponectin promoter. These animals were fed a high-fat diet to induce obesity and insulin resistance, then assessed by glucose tolerance tests, measurements of circulating factors, histological analyses of pancreatic islets, and glucose-stimulated insulin secretion assays on isolated islets.
Loss of GPS2 in adipocytes triggers inappropriate insulin secretion that promotes glucose intolerance in obese mice. This phenotype is driven by factors secreted by adipose tissue: ex vivo assays, in which pancreatic islets are exposed to medium conditioned by adipose explants from the deficient mice, show decreased insulin secretion in response to glucose. At the tissue level, these factors are accompanied by increased pancreatic islet inflammation and impaired beta-cell function.
This work thus reveals a previously unrecognized adipocyte role of GPS2: by controlling the reprogramming of white adipocytes, this coregulator remotely influences pancreatic islet function and insulin secretion, in both mice and humans, during the progression of obesity and type 2 diabetes.