Adiponectin and its role

Thousands of articles have been written on the adipokine adiponectin, describing its favourable properties in welfare-related diseases. It has been portrayed as anti-diabetic as well as protecting against the metabolic syndrome [1], cerebrovascular [2] and cardiovascular disease [3–6]. The degree of weight loss in correlation to circulating levels of adiponectin has been investigated in a recent article [7]. Dr Madsen and co-workers showed that the body weight in obese subjects must be lastingly reduced by at least 10 % to induce an increase in serum adiponectin after 3 years as compared to baseline. As the authors state, previous weight reduction studies have shown divergent results in terms of changes in adiponectin [1,8–11]. Even though it has been observed that studies showing no effect of weight loss on circulating adiponectin levels typically are characterized by a mean weight loss of v10 kg [12], a suggested threshold has not been demonstrated before in a prospective study. Nonetheless, three questions arise when adiponectin and weight loss are discussed. First, why do obese subjects in general have lower adiponectin levels compared to lean subjects in general? Second, what are the mechanisms at play behind these alterations, and third, why do the adiponectin levels actually increase in response to substantial weight loss? The spontaneous response to the first question could be that an increased adipose tissue per se causes low adiponectin levels. However, this has not been proved. In contrast, studies demonstrate a dissociation between the total amount or distribution of body fat and circulating adiponectin [13–15]. It has also been shown that obese subjects without the metabolic syndrome have the same adiponectin levels as a normal weight population [12]. In this study, obese subjects underwent a very low energy diet (VLED) and no correlation was seen between weight loss and the observed increase in serum adiponectin. Actually, the enhancement of serum adiponectin continued after the VLED when the weight did not decrease. Furthermore, in a study where women with normal glucose tolerance were BMI and WHR matched with women with impaired glucose tolerance, the former group had higher adiponectin levels [15]. Thus, it could be argued that obesity per se does not diminish adiponectin levels. The second question about the mechanisms behind the increase in adiponectin levels in weight loss is equally intriguing. If weight loss by itself does not correlate to raised adiponectin levels, other pathways must be involved. It could be assumed that the elevated levels of adiponectin are mirrored in a parallel boost in adiponectin mRNA expression. Nevertheless, this is not the case. In a study of obese subjects, the adipocyte adiponectin mRNA levels did not change during VLED in spite of a very clear augmentation in serum adiponectin [12]. In fact, this increase in serum adiponectin without changes in mRNA levels was also seen in this study during the 2 weeks after the VLED period when the subjects were weight stable. Accordingly, an increase in circulating adiponectin levels cannot be explained by changes in expression of the adiponectin gene. The third question, why adiponectin levels increase in response to weight loss, is perhaps just as captivating, but perchance not as puzzling. I have previously postulated that the adiponectin system has evolved in order to make the organism more adaptable to starvation [16]. This hypothesis has later been put forward by others [17]. This assumption presents a logical explanation for the high adiponectin levels seen in a broad range of catabolic states, encompassing severe cardiac [18] or renal failure [19], type 1 diabetes [20] and anorexia nervosa [21]. Furthermore, in a study by Dr Semple and colleagues, it was shown that humans with genetically defective insulin receptors have high adiponectin levels [22]. They have also demonstrated a dramatic increase of circulating