A systems biology analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo

Lipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge from in vitro systems have not been linked to corresponding in vivo data and knowledge in vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combining in vivo and in vitro data into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setups in silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.

The Role of GDF15 as a Myomitokine

Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15–GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.

Impact of Branched Chain Amino Acid Supplementation on Adipose Tissue Lipolysis

Objectives Branched chain amino acids (BCAAs), Valine, Leucine, and Isoleucine have been shown to impact adipose tissue physiology through regulation of adipocyte differentiation, lipogenesis, and lipolysis. Further, circulating BCAAs are elevated during obesity and insulin resistance, a characteristic attributed to impaired BCAA catabolic networks in adipose tissue and skeletal muscle. The objective of this study was to determine whether the induction of lipolysis in adipose tissue is a characteristic feature prompted by the chronic availability of BCAAs. Methods Mice (C57-BL6N) were kept on low-fat (LF, 10% fat calories; n = 9) and low-fat supplemented with 150% BCAA (LB; n = 10) diets for 34 weeks. Following an overnight fast (∼12–14 hrs), serum and perigonadal adipose (PGA) tissue samples were collected for metabolic analysis. Serum free fatty acids (FFAs) were analyzed and 25 milligrams (mg) of PGA was used for an in vitro lipolysis assay. Lipolysis in the PGA was induced under basal and isoproterenol (ISP, 10 micromolar, μM) stimulated conditions for 2 hours. In a second experiment, PGA tissue explants from normal mice (n = 18) were incubated with two levels of BCAA supplementation (500 μM and 1 millimolar, mM). FFAs in the incubation media were measured as an index of adipose tissue lipolysis. Results Overnight fasting body weights of the LF and LB mice remained similar. However, PGA tissue weights were significantly lower in the LB group (grams ± SEM; LF, 1.34 ± 0.09 vs LB, 0.84 ± 0.11, P = 0.003). LB serum FFAs were elevated (mM FFAs ± SEM; LF 0.73 ± 0.04 vs LB, 0.88 ± 0.04, P = 0.01). Basal lipolysis (mM FFAs/mg tissue protein ± SEM) trended to be higher in the PGA from the LB animals (LF, 1.44 ± 0.18 vs LB, 1.88 ± 0.15, P = 0.08). While ISP significantly induced lipolysis, the stimulated lipolytic rates remained similar between LF and LB groups. When normal PGA explants were challenged with BCAAs, the 1mM BCAA supplemented group tended to show higher fatty acid release (mM FFAs/mg tissue protein ± SEM; 500 μM, 0.89 ± 0.06 vs 1mM, 1.02 ± 0.05, P = 0.09). Conclusions In summary, these results suggest that BCAA mediated increases in adipose tissue lipolysis can contribute to circulating FFA levels. BCAA mediated lipolysis and the subsequent increase in circulating FFAs could indirectly modulate substrate oxidation in peripheral tissues including liver and muscle. Funding Sources NIH RO1