Overexpression of interleukin-15 in mice promotes resistance to diet-induced obesity, increased insulin sensitivity, and markers of oxidative skeletal muscle metabolism

Abstract

Interleukin-15 (IL-15) is a cytokine that is highly expressed in skeletal muscle. In addition to its well-characterized effects on innate immunity, IL-15 has been proposed to modulate skeletal muscle and adipose tissue mass, as well as insulin sensitivity. In the present study, an IL-15 gain-of-function model, transgenic mice with skeletal muscle-specific oversecretion of IL-15 (IL-15 Tg mice), was utilized to test the hypotheses that IL-15 promotes insulin sensitivity and resistance to diet-induced obesity (DIO) by increasing circulating adiponectin levels, and that IL-15 regulates skeletal muscle metabolism without inducing overt muscle hypertrophy. Compared to closely related control mice, IL-15 Tg mice exhibited lower total body fat following high-fat feeding, lower intra-abdominal fat following both low- and high-fat feeding, and greater insulin sensitivity. However, this was not accompanied by increased total or high molecular weight serum adiponectin levels in IL-15 Tg mice. While overall lean body mass did not differ, IL-15 Tg mice exhibited increased mass of the oxidative soleus muscle, and increased expression of mRNA encoding the slow isoform of troponin I (TnnI 1) in the predominately glycolytic extensor digitorum longus muscle. Skeletal muscle tissue from IL-15 Tg mice also exhibited alterations in the expression of several genes associated with fatty acid metabolism, such as SIRT1, SIRT4, and uncoupling protein 2 (UCP2). These findings suggest changes in oxidative metabolism, rather than induction of adiponectin expression, appear to be responsible for the DIO-resistant and more insulin-sensitive phenotype of IL-15 Tg mice.

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

“…Studies in humans support a role for IL-15 in the target tissues of patients with rheumatoid arthritis (62,63), autoimmune myositis (64), obesity (65), celiac disease (66), and multiple sclerosis (47,48). Exposure of lymphocytes such as CD8…”

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…During rapid growth, such as that experienced by T cells after antigenic stimulation, T cells switch their energy metabolism from favoring oxidative phosphorylation (TCA cycle) to aerobic glycolysis (43), a process that can be enhanced by IL-15 signaling through CD122 (44). Cells that are stuck favoring the TCA cycle and unable to meet increased energy demands are more likely to die from necroptosis (45).…”

IL-15Rα deficiency leads to mitochondrial and myofiber differences in fast mouse muscles

“…Recent work has demonstrated that genetic manipulation of IL-15 and IL-15Rα in vivo in the absence of exercise training results in a more oxidative muscle phenotype with functional changes similar to fatigue resistant skeletal muscles [6-8]. For example, in a transgenic mouse over-expressing IL-15 within skeletal muscle, increased expression of the slow isoform of troponin-c in the fast extensor digitotum longus (EDL) muscle along with greater expression of proteins associated with energy and metabolic homeostasis such as sirtuin1 (SIRT1), SIRT4, and uncoupling protein-2 (UCP2) were reported [8].…”

“…For example, in a transgenic mouse over-expressing IL-15 within skeletal muscle, increased expression of the slow isoform of troponin-c in the fast extensor digitotum longus (EDL) muscle along with greater expression of proteins associated with energy and metabolic homeostasis such as sirtuin1 (SIRT1), SIRT4, and uncoupling protein-2 (UCP2) were reported [8]. In the total tissue IL-15RαKO mouse, running wheel activity was 6-fold greater than control mice, and the fast EDL muscle displayed a resistance to contraction-induced fatigue.…”