Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose Tissues

Abstract

ObjectiveIL-15 is an inflammatory cytokine secreted by many cell types. IL-15 is also produced during physical exercise by skeletal muscle and has been reported to reduce weight gain in mice. Contrarily, our findings on IL-15 knockout (KO) mice indicate that IL-15 promotes obesity. The aim of this study is to investigate the mechanisms underlying the pro-obesity role of IL-15 in adipose tissues.MethodsControl and IL-15 KO mice were maintained on high fat diet (HFD) or normal control diet. After 16 weeks, body weight, adipose tissue and skeletal mass, serum lipid levels and gene/protein expression in the adipose tissues were evaluated. The effect of IL-15 on thermogenesis and oxygen consumption was also studied in primary cultures of adipocytes differentiated from mouse preadipocyte and human stem cells.ResultsOur results show that IL-15 deficiency prevents diet-induced weight gain and accumulation of lipids in visceral and subcutaneous white and brown adipose tissues. Gene expression analysis also revealed elevated expression of genes associated with adaptive thermogenesis in the brown and subcutaneous adipose tissues of IL-15 KO mice. Accordingly, oxygen consumption was increased in the brown adipocytes from IL-15 KO mice. In addition, IL-15 KO mice showed decreased expression of pro-inflammatory mediators in their adipose tissues.ConclusionsAbsence of IL-15 results in decreased accumulation of fat in the white adipose tissues and increased lipid utilization via adaptive thermogenesis. IL-15 also promotes inflammation in adipose tissues that could sustain chronic inflammation leading to obesity-associated metabolic syndrome.

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

“…The role of IL-15 in lipid accumulation is not clear and requires further investigation. Currently, it is known that IL-15 inhibition promotes attenuation of atherosclerotic lesions [51], and this interleukin is involved in inflammation in adipose tissues leading to obesity-associated metabolic syndrome [52]. Activation of the PAR2 receptor led to the upregulation of inflammatory gene expression and enhanced lipid accumulation in macrophages [53].…”

Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function

“…It seems that these effects of IL‐15 result from increased whole‐body energy metabolism, as IL‐15Rα −/− mice display increased oxygen consumption and utilization of muscle fatty acids (He et al ., ). These data were corroborated by findings that IL‐15 −/− mice presented decreased lipid accumulation in both white and BAT depots (Lacraz et al ., ).…”

Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors

“…Conversely, some differences exist, while IL15A KO mice are glucose intolerant and insulin resistant, independent of the diet and age [ 237 ], IL15 over-expression in muscle increases insulin sensitivity in HFD fed mice [ 231 ]. To complicate matters further, the previously reported obese IL15 KO mice [ 227 , 228 ] have recently been shown to resist diet induced overall AT accumulation, visceral AT inflammation and IR, through enhanced EE (discussed in detail below) [ 238 ].…”

“…Overall, these observations pose doubts regarding whether this cytokine exerts pathogenic or beneficial metabolic effects (i.e., promotion of EE, muscle performance and insulin sensitivity) and warrant further investigation. Various hypothesis has been raised to reconcile or rebut these findings: (1) increases in circulating free IL15 [ 210 , 237 ] and an IL15 induction of pro-inflammatory cytokines from resident immune cells in AT of IL15A KO mice [ 238 , 239 ] and (2) differences in the composition of gut microbiota between mouse strains [ 228 , 238 ].…”

“…As above mentioned, both muscle specific gain and global loss of function mutant mice showed elevated levels of whole-body EE; but postprandial increases in core body temperature, consistent with adaptive thermogenesis and independent of the fed diet, were only detected in null IL15RA [ 236 , 237 ] and IL15 mice [ 238 ]. The higher hypothalamic orexin and transient receptor potential vanilloid 4 cation channel ( TPRV4 ) gene expression observed in low fat diet (LFD) fed IL15RA deficient mice is consistent with a central role of this cytokine in thermoregulation and inhibition of BAT thermogenic activity.…”