Characterisation of Changes in the Adipose Tissue Proteome in Pre-clinical and Clinical Studies of Surgical and Medical Approaches to Obesity Therapy

Adipose tissue (AT) dysfunction occurs in parallel with increases in white AT mass in obesity, and the term ‘adiposopathy’ has been coined to describe the pathophysiology of AT dysfunction. It is postulated that in order for obesity interventions to cause remission of type 2 diabetes mellitus (T2DM) and prevention of other obesity-associated metabolic diseases, interventions must bring about improvement in adiposopathy in addition to reducing adiposity. Bariatric surgery displays the highest efficacy for weight loss and a reversal of adiposopathy may at least partly underlie the efficacy of this intervention. Characterizing changes in AT following weight loss may highlight AT-related improvements and help inform the development of new therapeutic modalities. The aim of this study was to characterize the AT proteome in both preclinical and clinical studies of surgical and medical interventions of obesity. Visceral AT from obese male Zucker Diabetic Sprague Dawley ZDSD rats (n = 33) was characterized across varying degrees of glycaemia. Animals with higher body weight at the beginning of the study displayed higher glycaemia at endpoints. Adipocytes were decreased in size in animals that displayed overt diabetes. Perturbation of adipocytokine mRNA expression was noted alongside increases in Tnf mRNA transcripts. At the proteomic level, the visceral AT in diabetic animals displayed a decreased abundance of mitochondrial proteins involved in aerobic respiration, and an increased abundance of complement cascade proteins. Following this, a cross-sectional weight loss intervention study was undertaken in a separate cohort of male ZDSD rats. The visceral AT proteomes were compared between animals that underwent medical therapy (n = 4), bariatric surgery (n = 8), a combination of surgery and medical therapy (n = 7), or a control sham laparotomy (n = 7). The interventions resulted in 20 – 30% weight loss, and stabilisation of glycaemia in animals. Across the interventions, changes were observed in abundance of proteins which indicated increased activity in processes related to metabolism of fatty acids, glucose and branched chain amino acids (BCAA). Surgery and medical therapy had differential effects upon complement cascade proteins; being increased by the former and decreased by the latter. The membrane attack complex inhibitor CD59 displayed the highest fold change increase in the surgery and the combined surgery and medical therapy groups. Next, subcutaneous AT biopsies originating from obesity patients (n = 37) that had underwent bariatric surgery as part of the RYSA clinical trial (NCT02882685) were obtained. Comparisons of the subcutaneous AT proteome at 6- and 12-months versus baseline revealed differences in abundance of proteins related to fatty acid and glucose handling between 6- and 12-months. Mitochondrial proteins were decreased at 6-months, and increased at 12-months. Increases in the abundance of proteins involved in the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation and BCAA catabolism were most pronounced at 12-months follow-up. CD59 displayed the highest fold change increase at 6- and 12-months. CD59 was detected by qPCR in rat visceral AT adipocytes and stromovascular cells and decreased in expression during adipocyte differentiation in vitro. Expression of the BCAA catabolic enzyme complex subunit BCKDHA positively correlated with percentage fat mass reduction in the RYSA study. Changes in the abundance of downstream branched chain fatty acids (BCFAs) were not detected, however, levels of BCFAs within AT were inversely correlated with expression rates of specific fatty acid oxidation enzymes. Together, this proteomic analysis improves the understanding of the proteomic profile of AT following significant weight loss, highlighting the temporal specificity of conserved cross-species changes in inflammatory and metabolic processes.