Role of adipose tissue as an endocrineorgan in systemic inflammation

Introduction The escalating public health problem represented by obesity has spurred multidisciplinary research into adipose tissue and importantly, the molecular biology of the adipocyte. The concept of adipose tissue as an endocrine organ, in addition to an energy storage compartment, is now pivotal in linking excess adiposity to disease states. Recent studies suggest that obesity related metabolic disorders are characterised by mild chronic inflammation as a result of adipocytokine production from fat tissue leading to dysregulation in the pro/anti‐inflammatory systemic balance. Adipokines and pro‐inflammatory markers are implicated in insulin insensitivity, blood glucose dysregulation, inflammation and atherosclerosis. There is a considerable amount of research into the characterization of adipokines and pro‐inflammatory cytokines, the antiinflammatory adipocytokines warrant further exploration. Research studies and design This PhD research was set out to investigate potential antiinflammatory molecules that could be used as markers of, and therapeutics for, metabolic syndrome associated maladies. This PhD consists of three studies including Study 1: a haracterisation study of pro/anti‐inflammatory mediators carried out on 116 men of various BMI and body composition; Study 2: an in vitro study design carried out in human Simpson Golabi Behmel Syndrome (SGBS) adipocyte cell line investigating a glucocorticoid regulated anti‐inflammatory protein, annexin A1 (AnxA1) and its role in fat tissue function; and Study 3: a double‐blind cross‐over randomised trial in 15 borderline metabolic syndrome males investigating the effect of a supplemental antiinflammatory agent, resveratrol (250 mg/day for two weeks, from 500 mg of Polygonum cuspidatum (from root)), on metabolic parameters. Key findings Study 1: We demonstrated for the first time that AnxA1 is significantly inversely correlated with increasing BMI (R = ‐0.424**, P < 0.001), increasing body fat % (R = ‐0.192, P = 0.037) and a larger waist size (R = ‐0.390**, P < 0.001) in 118 men aged 19 to 61 years, with BMI between 16.8 – 56.4 kg/m2, BF % between 4.3 to 51.8 %. The negative correlation of decreasing plasma AnxA1 was strongest statistically when compared with WHR, rather than total body fat, suggesting that centrally located fat may be more influential at reducing plasma AnxA1 concentrations. Study 2: We have shown that ANXA1 gene is expressed in human SGBS adipocytes and hypoxia reduces the expression of ANXA1 gene showing that AnxA1 may act as a counter regulator of adipose tissue inflammation. We found that CRP expression was significantly down‐regulated following 4 (P=0.015), 8 (P=0.035) and 24 (P=0.037) of hypoxia treatment in the cells also treated with Ac2‐26 peptide compared to vehicle alone. IL‐6 was also found to be significantly down‐regulated after 24 hour hypoxia treatment in the Ac2‐26 treated cells compared to vehicle (P=0.022). Study 3: The effect of resveratrol on metabolic function had no significant effect on the metabolic markers measured including blood pressure, blood glucose, blood cholesterol and glycated LDL. Conclusion: These data demonstrate that AnxA1 could potentially represent a (fat) depot specific biomarker whose decline with increasing central adiposity may relate to the phenomena of increasing systemic inflammation and associated disease risk. We also demonstrate for the first time that an AnxA1 is expressed in human SGBS preadipocytes and mature adipocytes and AnxA1 mimetic, Ac2‐26 peptide, regulates pro‐inflammatory markers in human SGBS adipocytes. We showed that it may be difficult to improve the metabolic profile of individuals through supplementation of exogenous anti‐inflammatory agent, resveratrol. Whilst anti‐inflammatory agents such as AnxA1 may propose novel therapeutics for metabolic syndrome associated diseases, to date regular exercise and weight loss remain the main interventions that significantly cut the risk of developing chronic long‐term conditions and obesity‐associated maladies