Human Peripancreatic Fat Secretome Impacts Local Pancreas Biology

Obesity and metabolic diseases such as T2D are an important cause of human morbidity. Although whole body adiposity is associated with metabolic dysfunction, different fat depots have markedly divergent impacts on lipotoxicity and glucose homeostasis: subcutaneous adipose tissue (SAT) is generally protective, but visceral adipose tissue (VAT) is harmful. Pancreas-associated fat, including intracellular fat, intra-islet fat, intrapancreatic fat, and peripancreatic fat, may be particularly diabetogenic by altering insulin resistance, insulin secretion, inflammation, and oxidative stress (1, 2). However, due to the fundamental challenges of studying pancreas biology in living humans, existing studies have been correlative in nature, comparing metabolic physiology across individuals with radiologically quantified pancreas fat, leaving a major gap in knowledge regarding specific mechanisms by which pancreas-associated adipose tissue increases diabetes risk. Bergman et al (3) have performed a creative and ambitious study seeking to identify the molecular mechanisms driving diabetogenic damage caused by peripancreatic adipose tissue (PAT). Live PAT obtained from the Human Pancreas Analysis Program (4) was compared against surgically obtained SAT in several impactful assays. Conditioned media was assessed for secreted factors such as inflammatory cytokines, adipokines, eicosanoids, and lipids. Beyond simply characterizing the PAT secretome, the authors assessed the impact of PAT-secreted factors on key functional outcomes such as insulin secretion, islet transcriptome, and aortic ring vasoreactivity. The results point to intriguing possible causes of PAT diabetogenicity.