This study examined the relation of adiponectin levels alone or normalized by leptin to metabolic risk factors for cardiovascular disease including markers of atherogenic dyslipidemia (levels of plasma triglyceride and HDL cholesterol and ratios of plasma triglyceride/HDL cholesterol) and insulin resistance (levels of HOMA2-IR) in men. The key observations made in this study were that high levels of adiponectin were associated with lower plasma triglycerides, higher HDL cholesterol, reduced ratios of triglyceride/HDL cholesterol, and reduced HOMA2-IR compared to lower levels of adiponectin in men regardless of waist girth. Normalizing adiponectin levels by leptin enhanced the associations of adiponectin to the metabolic risk factors. That is, subjects with a high ratio of adiponectin/leptin had lower triglycerides and triglyceride/HDL cholesterol ratios and higher HDL cholesterol and insulin sensitivity than those with low ratios of adiponectin/leptin regardless of waist girth. Thus, the adiponectin/leptin ratio was a useful index for identification of overweight and obese subjects with lower susceptibility to metabolic risk compared to individuals with a higher susceptibility.
Both adiponectin and leptin have been implicated in the causation of dyslipidemia and insulin resistance. For example, leptin deficiency is associated with hypertriglyceridemia, low HDL C, and low insulin sensitivity in cases of acquired or congenital lipodystrophies [18
]; leptin therapy reverses the metabolic dysfunction [19
]. But in obese subjects, leptin does not have an effect [20
]. Instead, leptin correlates with fat mass and it can be viewed as a biomarker of fat cell mass. Plasma levels of leptin generally reflect secretion rates by subcutaneous adipose tissue, principally by large adipocytes [9
]. Omental fat also secretes leptin, but the subcutaneous fat is thought to be a major source of leptin. This hormone is known to modulate energy homeostasis through its action on hypothalamic receptors where it inhibits appetite [21
]. Mutations in the human leptin gene are associated with hypogonadism and morbid obesity [22
], and mutations in the human leptin receptor gene causes obesity and pituitary dysfunction [23
]. Leptin replacement in obese subjects with leptin deficiency reverses the metabolic consequences of the deficiency in the hypothalamus [24
In the current study, the linear association between plasma levels of leptin and waist girth provided a rationale for using leptin as a surrogate of fat mass. Moreover, overweight and obese men showed considerable interindividual variation in leptin levels despite the high correlation with waist girth. The interindividual variation also suggested that leptin levels are probably a more specific measure of fat mass than waist girth. For these reasons, leptin was used to normalize levels of adiponectin.
In contrast to leptin levels, plasma levels of adiponectin were not strongly correlated with waist girth. Others have shown an inverse association of adiponectin with total body fat [25
]. However, the current study population showed a marked heterogeneity in plasma adiponectin level and this proved to be instructive. At any waist girth category, it was clear that there were men with high and low adiponectin levels. Thus, two questions could be addressed readily: (1) are there differences in levels of metabolic risk factors between men with high and low adiponectin levels regardless of waist girth? (2) If adiponectin levels are “normalized” for leptin levels, are the differences in metabolic risk factors better defined by the ratio of adiponectin/leptin than adiponectin alone?
The levels of plasma triglyceride were lower in men with a high adiponectin than in those with a low adiponectin. In contrast, HDL C, levels were higher in men who had high adiponectin compared with those with low adiponectin. Similarly, low ratios of plasma triglyceride/HDL C were lower in men with high adiponectin compared with those with low adiponectin. After normalizing adiponectin levels by leptin, the impact of the ratio of adiponectin/leptin on triglyceride, HDL C, and the ratio of triglyceride to HDL C was more apparent. The ratio segregated overweight and obese subjects into those with a relatively healthier metabolic profile and those with a higher-risk profile. Still the average plasma triglyceride levels of overweight and obese men with a high ratio of adiponectin/leptin were somewhat higher than the cut point of at-risk triglyceride (150
mg/dL). Perhaps a higher adiponectin/leptin ratio is needed to optimize triglyceride levels.
In contrast to leptin, adiponectin levels may be indicative of a protective effect of the adipokine on triglyceride metabolism even in the presence of excess body fat. Studies in animals suggest that adiponectin reduces levels of plasma triglyceride by increasing VLDL-triglyceride hydrolysis mediated by lipoprotein lipase [26
]. Transgenic mice overexpressing adiponectin show a reduction in plasma triglycerides compared to wildtype [27
] while adiponectin knockout mice have increased plasma triglycerides. These data suggest that adiponectin has a direct effect on triglyceride hydrolysis [30
]. Other studies also suggest that adiponectin is an insulin sensitizer and it could exert a hypotriglyceridemic effect under such conditions. The association of adiponectin with HDL cholesterol may result from its hypotriglyceridemic effect or it could be the result of the effect of adiponectin on either apo A-I fractional catabolic rate [31
] or a direct effect of adiponectin on hepatic lipase [33
In the current study, high adiponectin levels also were generally associated with higher insulin sensitivity measured by HOMA2-IR than low adiponectin levels. This effect is supportive of the view that adiponectin is an insulin sensitizer [35
]. As such the adipokine can modulate the metabolism of triglycerides, HDL, and glucose. The exact mechanisms of the insulin sensitizing effect of adiponectin are not clearly understood. But in this study, it was clear that adiponectin and, more specifically, the ratio of adiponectin/leptin were a good indicator of insulin sensitivity in overweight and obese men.
The adiponectin/leptin ratio also was shown to decrease with the increasing number of metabolic risk factors for cardiovascular disease (). This ratio may be useful to identify subjects susceptible to metabolic risk, and adiponectin/leptin ratios may reflect the functionality of adipose tissue. Accordingly, two metabolic phenotypes were identified in overweight and obese subjects in the current study. It has been suggested that subjects are heterogeneous in the prevalence of metabolic risk factors. Some nonobese subjects have “metabolic obesity” [37
]. Other investigators have identified obese subjects with a low prevalence of metabolic alterations which they have designated as “metabolically healthy” or “unhealthy” [38
]. In the current study, the individuals with the high ratio of adiponectin/leptin had less dyslipidemia and insulin resistance than those with the low ratio, but they were not free of other risk factors. The ratio, however, suggested that adiponectin levels relative to leptin may be indices of susceptibility to metabolic risk.