Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

Abstract

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the pro-inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

What Is the Role of Inflammatory Mediators on Energy Metabolism?

“…In this study, the IL-15 treatment decreased WAT and BAT (35% and 24%, respectively). So, IL-15 can induce the BAT energy expenditure, through thermogenesis, which supports a mechanism to IL-15 action on obesity control [30] . According to Barra et al [42] obese individuals have smaller IL-15 concentrations than eutrophic individuals.…”

“…So, this favors an increase in energy expenditure and WAT reduction, besides modulates the body composition and, therefore, prevents the obesity and disorders related to such disease [27][28][29] . In this way, in a study proposed by Ye [30] , the IL-15 administration increased the UCPs expression, promoting thermogenesis -one of the mechanisms which induces energy expenditure, and consequently inhibit obesity [20,31] .…”

“…Such cytokine exerts anti-inflammatory action on adipose tissue, playing pleiotropic functions, by apoptosis stimulation and its capacity to modulate the metabolism, and pro-inflammatory function since it promotes the IFN-γ expression, which amplifies the inflammation. The IL-15 mRNA is highly expressed in skeletal muscle tissue, thus it has a greater function as an endocrine factor, which may be associated with energy metabolism and, consequently, to the body composition modulation [30,39,40] .…”

“…It is believed that IL-15 has the ability to modulate the body composition by exerts direct effects on the carbohydrates and lipids metabolism, as well as on the insulin sensitivity fatty acid oxidation, lipogenesis inhibition, very low density lipoprotein decrease (VLDL) and thermogenesis promotion [30,35,37,40,41] .…”

Obesity Induced Inflammation – A Complex Condition

“…IL-15 activates inflammationassociated pathways including IKK/NF-κ B, JAK/STAT and PI3K/Akt. 10 Accordingly, it seems that one of the reasons that many anti-inflammatory therapies did not show expected efficacy might be the simultaneous reduction of the advantages of inflammation.…”