Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro

Abstract

. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab 288: E155-E162, 2005. First published September 21, 2004; doi:10.1152/ ajpendo.00257.2004.-To determine whether IL-6 increases lipolysis and fat oxidation in patients with type 2 diabetes and/or whether it exerts this effect independently of changes to the hormonal milieu, patients with type 2 diabetes (D) and healthy control subjects (CON) underwent recombinant human (rh)IL-6 infusion for 3 h. Rates of appearance (Ra) and disappearance (Rd) of [U-13 C]palmitate and [6,6-2 H2]glucose were determined. rhIL-6 infusion increased (P Ͻ 0.05) palmitate Ra and Rd in a similar fashion in both groups. Neither plasma glucose concentration nor glucose Ra/Rd was affected by rhIL-6 infusion in either group, whereas rhIL-6 infusion resulted in a reduction (P Ͻ 0.05) in circulating insulin in D. Plasma growth hormone (GH) was increased (P Ͻ 0.05) by IL-6 in CON, and cortisol increased (P Ͻ 0.05) in response to IL-6 in both groups. To determine whether IL-6 was exerting its effect directly or through activation of these hormones, we performed cell culture experiments. Fully differentiated 3T3-L1 adipocytes were treated with PBS (control) IL-6, or IL-6 plus dexamethasone and GH. IL-6 treatment alone increased (P Ͻ 0.05) lipolysis, but this effect was reduced by the addition of dexamethasone and GH such that IL-6 plus dexamethasone and GH had blunted (P Ͻ 0.05) lipolysis compared with IL-6 alone. To assess whether IL-6 increases fat oxidation, L6 myotubes were treated with PBS (Control), IL-6, or AICAR, a compound known to increase lipid oxidation. Both IL-6 and AICAR markedly increased (P Ͻ 0.05) oxidation of [ 14 C]palmitate compared with Control. Acute IL-6 treatment increased fatty acid turnover in D patients as well as healthy CON subjects. Moreover, IL-6 appears to be activating lipolysis independently of elevations in GH and/or cortisol and appears to be a potent catalyst for fat oxidation in muscle cells. cytokines; metabolism; insulin sensitivity THE CYTOKINE INTERLEUKIN-6 (IL-6) has traditionally been known for its immunomodulatory effects, but recent research has focused on its metabolic role in the etiology of obesity and type 2 diabetes. Studies have demonstrated that acute IL-6 administration can alter fat metabolism and lipolysis. We (28) and others (13) have demonstrated that the infusion of recombinant human (rh)IL-6 into healthy humans increases whole body lipolysis and free fatty acid (FFA) oxidation. In addition, Wallenius et al. (30) recently demonstrated that an IL-6 knockout mouse became obese, a phenotype which was partially reduced with IL-6 treatment. Hence, it has been suggested that IL-6 is a possible target therapy for obesity-related disorders (30). In line with altered fatty acid metabolism, the effect of IL-6 on insulin sensitivity is not completely clear, since a number of both in vitro and in vivo studies have demonstrated that IL-6 decreases (3,10,11,18,2...

IL-6 regulates adipose deposition and homeostasis in lymphedema

“…This finding is important since it suggests that the degree of lymphatic injury is a critical regulator of IL-6 expression. This hypothesis is supported by previous studies demonstrating that adipose tissues are a major source of circulating IL-6 levels (14,26) and that IL-6 functions as an adipolytic cytokine regulating circulating levels of fatty acids (19,22,23,29,34,36).…”

“…For example, the expression of IL-6 has been shown to correlate with adipose tissue depots in obese patients accounting for as much as 15-30% of circulating IL-6 levels (14,26). Furthermore, recombinant human IL-6 administration has been shown to increase lipolysis and fatty acid oxidation in human subjects as well as in vitro adipose cultures (19,23,29,34). In addition, previous studies have shown that the expression of IL-6 is increased in both primary and surgical models of lymphedema (20,28).…”

Myokines in insulin resistance and type 2 diabetes

“…Interestingly, no effect on adipose tissue lipolysis was found [31], suggesting that IL-6 primary acts locally within muscle tissue on fatty acid metabolism. As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation …”

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

“…In vitro and ex vivo, acute IL-6 treatment can enhance glucose uptake and fat oxidation [5][6][7][8][9] in skeletal muscle, principally via activation of AMP-activated protein kinase [7]. Acute IL-6 administration during a euglycaemic-hyperinsulinaemic clamp results in a glucose infusion rate that is either unchanged in rats [10,11], decreased in mice [12] or increased in humans [7].…”