European Journal of Clinical Nutrition (2013) 67, 485–491 & 2013 Macmillan Publishers Limited All rights reserved 0954-3007/13 www.nature.com/ejcn REVIEW Factors determining the risk of the metabolic syndrome: is there a central role for adiponectin? EK Calton, VS Miller and MJ Soares BACKGROUND AND OBJECTIVES: The pathogenesis of the metabolic syndrome (MetS) is not well understood. This review is based on the hypothesis that both traditional and emerging risk factors act through adiponectin. SUBJECTS AND METHODS: We conducted a search of the literature using prominent electronic databases and search terms that included in combination: adiponectin, diet, dietary patterns, exercise, metabolic rate, MetS and testosterone. Articles were restricted to studies conducted on adult humans, reported in English and within the time period 2000–2012. RESULTS AND CONCLUSIONS: Both traditional and emerging risk factors associated with the MetS show some evidence of exerting their influence through adiponectin. High-quality randomized controlled trials that alter adiponectin levels are required to further corroborate this hypothesis. European Journal of Clinical Nutrition (2013) 67, 485–491; doi:10.1038/ejcn.2013.1; published online 30 January 2013 Keywords: metabolic syndrome; adiponectin; diet; vitamin D; basal metabolic rate; mitochondria INTRODUCTION several factors on MetS risk through adiponectin (Figure 1). We The metabolic syndrome (MetS) represents a clustering of risk also investigate the outcomes from randomized controlled trials factors for cardiovascular disease and type 2 diabetes mellitus on circulating adiponectin and the associated benefits on (T2DM), which include: hypertension, low high-density lipoprotein- components of the MetS (Table 1). cholesterol (HDL-C), high triglycerides (TG), high fasting blood glucose (FBG) and abdominal obesity.1 Obesity and insulin resistance (IR) have long been accepted as having a pivotal role METHODS in the etiopathogenesis of the syndrome.2,3 However, emerging We conducted a literature review of the following electronic databases: evidence indicates that even after controlling for these variables, Cambridge University Press Journals Complete, Proquest Central, PubMed there remains a substantial unexplained risk.2,4–6 Central, Science Direct and Wiley Online Library. Individual Journals were Adiponectin, a collagen-like protein was first discovered in 1995 also searched for relevant studies, these included: American Journal of Clinical Nutrition, Cardiovascular and Metabolic Risk, Circulation Journal, by Dcherer and Lodish, who called it adipocyte complement- 7 Diabetologia, European Journal of Clinical Nutrition, Journal of Clinical related protein of 30 kDa (Acrp30). At a similar time, three other Endocrinology and Metabolism, Metabolism, Clinical and Experimental and independent groups discovered adiponectin, calling it adipose Obesity Journal. Articles were restricted to the English language, studies most abundant gene transcript 1 (apM1), AdipoQ and gelatin- conducted with adult humans and within the time period 2000–2012. The binding protein of 28 kDa (GBP28).8 Adiponectin is secreted following key words in various combinations were used: adiponectin, diet, primarily from adipose tissue into the circulation where high- dietary patterns, exercise, metabolic rate, MetS and testosterone. molecular-weight, medium-molecular-weight and low-molecular- weight oligomeric forms exist.8,9 Total adiponectin as well as the individual oligomeric forms have been associated with health RESULTS benefits.9 Consistent links between low adiponectin levels and Adiposity, inflammation, IR and the MetS increased TG, FBG, waist circumference, blood pressure (BP) levels Adipose tissue is now recognized as an active organ, and not as an and decreased HDL-C explain its potential role in the etiology of inert store of excess lipid as once believed.7 Adipose tissue secre- MetS.2,10 Furthermore, genetic studies have linked adiponectin tes a variety of bioactive adipocytokines, many of which are and MetS in individuals of European descent.11 Specifically, overall proinflammatory. It is widely accepted that the abnormal inflam- adiposity, abdominal adiposity and IR were influenced by gene matory profile observed in obesity is secondary to adipocyte loci, which also encode adiponectin.12 hypertrophy (increase in cell size) caused by the storage of excess This review discusses both traditional and emerging factors that lipid.15 Recently, chronic low-grade inflammation, otherwise may influence the prevalence of MetS. Furthermore, the possibility known as meta-inflammation, has been implicated as a major that adiponectin may have an important role in the pathogenesis factor in the development of the syndrome. Evidence of a of the syndrome was evaluated. As there is inconsistency proinflammatory state in MetS comes from the observation of in the literature whether total, high-molecular-weight, medium- elevated concentrations of a variety of inflammatory molecules molecular-weight or low-molecular-weight adiponectin was mea- such as C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), sured,4,13,14 this review discusses adiponectin in general terms. We resistin, interleukins (IL-6, IL-8) and visfatin.16 In general, as the present a model that emphasizes the flow-through effects of number of MetS components observed increase, levels of Discipline of Nutrition and Dietetics, School of Public Health, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia. Correspondence: Professor MJ Soares, Discipline of Nutrition and Dietetics, Curtin Health Innovation Research Institute, School of Public Health, Curtin University, Perth, WA 6845, Australia. E-mail: [email protected] Received 6 August 2012; revised 12 December 2012; accepted 26 December 2012; published online 30 January 2013 Adiponectin and the metabolic syndrome EK Calton et al 486 Female Diet (↑dairy, ↑Vitamin D/ ↓BMR/↑Mitochondrial ↓Age ↑PA gender/↓TT low GL) ↓PTH function (3) (4) (5) (2) (1) (6) ↑ ADIPONECTIN (↓ adiponectin resistance) (7) ↓ Inflammatory response (8) ↑ Insulin sensitivity (9) ↓ METABOLIC SYNDROME Figure 1. Schematic of factors that influence MetS risk through adiponectin. (1) ¼ Van Berendoncks et al.48; (2) ¼ Ryo et al.2, Cnop et al.19, Kern et al.27; (3) ¼ Jurimae et al.59; (4) ¼ Yu et al.29, Pischon et al.49, Zemel et al.53; (5) ¼ Vaidya et al.65, Nimitphong et al.66; (6) ¼ Ruige et al.21, Schrauwen-Hinderling et al.72, Larsen et al.75 (7) ¼ Lara-Castro et al.9, Hamilton et al.14, Baratta et al.23, Hotta et al.24; (8) ¼ Sharma 18; (9) Ryo et al.2, Beavers et al.3,Xuet al.17 BMR, basal metabolic rate; GL, glycemic load; PA, physical activity; PTH, parathyroid hormone; TT, testosterone; m, increased; k, decreased. inflammatory markers increase. Furthermore, individual enhances the production of anti-inflammatory cytokines by inflammatory markers are associated with specific components macrophages, monocytes and dendritic cells.25 Numerous of MetS.16 In addition, greater adipose tissue leads to greater studies have found proinflammatory cytokines and adiponectin circulating fatty acids, which results in IR.17 In turn, IR leads to (an anti-inflammatory cytokine), to inhibit each other’s expression increased hepatic TG synthesis (increased very-low-density lipo- and secretion.9,15,26 protein in circulation) and increased HDL-C uptake from the Similarly, there is significant evidence of an inverse association circulation (due to changed HDL-C composition secondary to between adiponectin and IR. Several cross-sectional studies have increased very-low-density lipoprotein). IR also results in increased found adiponectin to be significantly and negatively correlated blood glucose due to increased hepatic glucose production, with IR21,24 and positively correlated with insulin sensitivity decreased glucose uptake by insulin-sensitive tissues and (IS).19,22,24 Furthermore, this relationship has been shown to be increases in BP secondary to salt reabsorption in the kidney.17 independent of gender, age and body mass index (BMI).27,28 Furthermore, it has been opined that IR may be responsible for Intervention trials with a variety of insulin-sensitizing drugs have increased inflammatory cytokine production in both the liver and resulted in increased adiponectin without changes in BMI; thus, adipose tissue.18 Thus, there is a considerable body of evidence adiponectin may be at least partly responsible for the insulin- implicating adiposity-induced IR and inflammation in the sensitizing benefits of these drugs.29–31 A 3-month intervention pathogenesis of the MetS (Figure 1). study29 with a specific thiazolidinedione (TZD) showed significant increases in adiponectin levels with improvements in fasting blood glucose, HDL-C and TG levels (Table 1). Furthermore, Does adiponectin have a role? thiazolidinediones have been shown to act directly on adipocytes, Adiponectin has repeatedly been shown to be inversely related to increasing adiponectin production as well as ameliorating the both adiposity and inflammatory cytokines through a variety of inhibitory effect of TNF-a on adiponectin expression.8 Adiponectin study designs, including cross-sectional, case–control and inter- receptors are found in microvascular endothelial cells, liver and vention studies.4,19–22 Intra-abdominal fat has been shown to be pancreatic b-cells.8 While the significance is not well understood, it negatively related to circulating concentrations of adiponectin in is possible that