Adipose Tissue IL-6 Content Correlates with Resistance to Insulin Activation of Glucose Uptake both in Vivo and in Vitro

Abstract

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.

Role of amyloid β in the induction of lipolysis and secretion of adipokines from human adipose tissue

“…Ab [25][26][27][28][29][30][31][32][33][34][35] has no effect on glycerol release at 2, 6, 12 h (data not shown). H89, a well-recognized inhibitor of PKA 26 partially inhibited Ab 25-35 induced glycerol release (P < 0.05 vs. Ab 25-35 alone).…”

“…H89, a well-recognized inhibitor of PKA 26 partially inhibited Ab 25-35 induced glycerol release (P < 0.05 vs. Ab 25-35 alone). Similarly, PD98059, an inhibitor of ERK1/2 27 also partially inhibited Ab [25][26][27][28][29][30][31][32][33][34][35] induced glycerol release (P < 0.05 vs. Ab 25-35 alone).…”

“…Ab [25][26][27][28][29][30][31][32][33][34][35] is the main functional domain of the Ab molecule that is required for neurotoxic effects. 28 We found that Ab [25][26][27][28][29][30][31][32][33][34][35] can induce lipolysis in cultured adipose tissue in a manner that appeared partially dependent on PKA and ERK1/2-dependent signaling pathways. Lipolysis for the provisions of fatty acids as a fuel for other tissues is a unique function of adipose.…”

“…30 Similarly, chronic low-grade elevations of IL-6 in adipose tissue are posited to directly contribute to insulin resistance. [31][32] Given the previous associations between adipose tissue APP and Ab in rodent models of obesity, the induction of leptin and IL-6 secretion by Ab [25][26][27][28][29][30][31][32][33][34][35] may indicate that Ab might contribute to adipose tissue inflammation and promote insulin resistance. It should be noted that in the present study we assessed the impact of aggregated Ab on cultured human adipose tissue.…”

“…Alternative peptides can be derived from cleavage at the C-terminus including Ab , Ab , Ab and Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Ab [25][26][27][28][29][30][31][32][33][34][35] is derived from cleavage at both termini, and is considered the core functional domain of Ab peptides. 3 Although much of the study of APP and Ab has focused on changes in the central nervous system during AD pathology, as early as in 1989 Joachim et al 4 reported that APP protein and mRNA are expressed in other tissues besides brain including adipose tissue, heart, muscle, kidney, liver, spleen, skin and intestine.…”