IL-15 : A NOVEL REGULATOR OF LIPOLYSIS IN HUMANS?

Abstract

Interactions between and within organ systems such as skeletal muscle (SkM) and adipose tissue (AT), via immune cell signaling factors (cytokines), may regulate the development of obesity. The increased expression and concentration of one of these cytokines, interleukin (IL)-15, has resulted in significant decreases in AT mass in animals, through the existence of an endocrine-like (SkM-blood-AT) axis. Studies further indicate that these IL-15-mediated decreases in AT mass can occur through reduced lipid uptake or by increased triglyceride breakdown (lipolysis) and release of degradation products from fat cells. While it is speculated that a similar endocrine axis exists in humans, most studies investigating these IL-15 and AT interactions are in animal and cell models: the impact of IL-15 on human AT remains unknown. Therefore, the global aim of this dissertation was to determine if local SkM and subcutaneous (SC) AT IL-15 sources contribute to circulating IL-15, and to examine if IL-15 induces SCAT lipolysis in humans. A secondary aim was to determine if these sources and lipolytic actions of IL-15 differ between lean (LN) and obese (OB) humans. Healthy LN (n=10, BMI = 23.1 ± 1.9 kg·m⁻², age: 24.0 ± 3.7 yr) and OB (n=10, BMI = 34.7 ± 3.5 kg·m⁻², age: 27.3 ± 9.1) men and women participated in the two studies presented in this dissertation. In the first study, using microdialysis probes (CMA/20: 100 kDa cutoff dialysis membrane) inserted in SkM and SCAT to sample interstitial IL-15, and an I.V. catheter to sample plasma IL-15, we examined local and systemic IL-15 concentrations and their correlation with SCAT lipolysis. In order to clarify how these correlations might change during exercise, subjects cycled for 1-hr at 60% of their heart rate reserve. In the second study using SCAT microdialysis probes, we perfused SCAT with IL-15 to assess direct IL-15 lipolytic effects, and to assess if this lipolytic response was different between LN and OB humans. We found that SkM interstitial IL-15 was not different between LN and OB, but that SCAT interstitial IL-15 was higher in OB than in LN subjects. Interestingly, SCAT interstitial IL-15 was positively correlated with SCAT lipolysis. Exercise increased plasma IL-15 in both LN and OB, and this increase was higher in OB than in LN subjects. Despite the expected exercise-induced increase in SCAT lipolysis, this increase was not different between LN and OB, nor correlated with IL-15 changes in plasma or SCAT IL-15. In the second study, we found that IL-15 resulted in increased lipolysis in LN individuals and suppressed lipolysis in OB individuals. Importantly, both of these responses occurred at concentrations likely to occur in vivo in AT, and occurred without any marked changes in blood flow. Our findings do not support the existence of an IL-15 endocrine axis in humans, but rather support the possible existence of an uninvestigated IL-15 autocrine/paracrine axis in human AT. In this paradigm, IL-15 may be produced in, and act on the same subcutaneous adipose tissue depot. Although we have found apparent differential regulation of SCAT lipolysis by IL-15 in lean and obese individuals, the extent to which this local axis regulates human body composition remains to be determined.