Leptin-mediated inflammatory signaling crucially links visceral fat inflammation to obesity-associated β-cell dysfunction

Abstract

AimThis study aimed to examine the causal relationship between adipokines released from visceral fat and pancreatic β-cell dysfunction in the state of obesity inflammation. Main methodsAdipose tissue and adipocyte conditioned medium were obtained from epididymal fat of B6 mice on regular or high fat diet for 16weeks. The latter were classified into two groups: overweight (OW, 40±2g) and obese (OB, 50±2g). Isolated mouse islets and NIT-1 cells were used to evaluate β-cell function. Key findingsFasting glucose, leptin, and interleukin-6 levels were increased in OW mice and were further elevated in OB mice. Adipocyte size and number of adipose macrophage infiltrations showed a similar trend. The augmentation of homeostasis model assessment of insulin resistance, islet hyperplasia and macrophage infiltration was noted only in OB mice. The stimulation index was lower, but reactive oxygen species production was higher in islets isolated from OB mice than from controls. In epididymal fat conditioned medium, the increases in leptin, IL-6 and TNF-α production in OW mice were further elevated in OB mice except TNF-α. Adipose tissue conditioned medium suppressed the stimulation index of islets isolated from B6 mice but not from db/db mice. The suppressive effect was also reversed by co-treatment with N-acetylcysteine or NS-398 (a selective cyclooxygenase-2 inhibitor). SignificanceA markedly elevated leptin production from inflamed visceral fat could deteriorate β-cell function via leptin receptor-mediated oxidative stress and cyclooxygenase-2 activation in the development of obesity.