Merja Santaniemi

Adiponectin: a link between excess adiposity and associated comorbidities?

Abstract. Adiponectin is a novel polypeptide that is highly specific to adipose tissue. In contrast to other adipocytokines, adiponectin levels are decreased in obesity and associated comorbidities, such as type 2 diabetes. Decreased expression of adiponectin is correlated with insulin resistance. It has been suggested that several agents, such as tumor necrosis factor α, could mediate their effects on insulin metabolism through modulating adiponectin secretion from adipocytes. The mechanisms for the development of atherosclerotic vascular disease in obese individuals are largely unknown. Several findings support the interesting hypothesis that adiponectin could be a link between obesity and related atherosclerosis. First, adiponectin levels are lower in patients with coronary artery disease. Second, adiponectin modulates endothelial function and has an inhibitory effect on vascular smooth muscle cell proliferation. Moreover, adiponectin is accumulated more preferably to the injured vascular wall than intact vessels and has been shown to suppress macrophage-to-foam cell transformation. Adiponectin may also be involved in the modulation of inflammation. Thiazolidinediones, antiatherogenic and other effects have been explained by their direct enhancing effect on adiponectin. In conclusion, adiponectin has anti-inflammatory and antiatherogeneic effects as well as multiple beneficial effects on metabolism. Therefore it is not a surprise that adiponectin therapy has been tested in animal models of obesity, and it has been shown to ameliorate hyperglycemia and hyperinsulinemia without inducing weight gain or even inducing weight loss in some studies. Unlike agents that exert their effects centrally, adiponectins effects seem to be peripherally mediated. The evidence of an association between adiponectin and the metabolic and cardiovascular complications of obesity is growing all the time.

Low serum adiponectin level as a predictor of impaired glucose regulation and type 2 diabetes mellitus in a middle-aged Finnish population

Low levels of adiponectin are associated with obesity and type 2 diabetes mellitus (DM2). However, only few studies on this topic have used the most recent World Health Organization 1999 criteria, which include a definition of impaired glucose regulation (IGR). Our objective was to find out if a baseline low adiponectin level in initially normoglycemic subjects predicted IGR or DM2 during a mean follow-up period of 5.1 years. A population-based cohort study was carried out in Oulu, Northern Finland. Subjects born in 1935 and living in Oulu in 1990 were invited to participate in a follow-up study. At baseline, oral glucose tolerance tests and measurements of adiponectin, lipids, blood pressure, and body mass index were performed; and oral glucose tolerance tests were repeated at follow-up. Analyses were performed for 201 subjects who were normoglycemic at baseline. Low adiponectin level was defined as the lowest quartile of adiponectin levels. During the follow-up, 47 (23%) of the 201 subjects developed IGR or DM2. Impaired glucose regulation or DM2 developed in 15 of 41 (37%) subjects with low adiponectin level at baseline, whereas the corresponding proportion was 32 of 160 (20%) subjects with higher adiponectin levels (P = .025). In logistic regression analysis, the adjusted odds ratio for IGR or DM2 was 2.1 (95% confidence interval, 1.0-4.5) when adjustment was made for sex and body mass index. Low concentrations of adiponectin predicted subsequent development of IGR and DM2 in initially normoglycemic middle-aged Finnish subjects. Our findings support the hypothesis that adiponectin may play a role in the pathogenesis of abnormal glucose metabolism.

Adiponectin polymorphisms, adiposity and insulin metabolism: HERITAGE family study and Oulu diabetic study

Aims/hypothesis. Adiponectin is an adipocytokine with lowered blood levels in obesity and Type 2 diabetes mellitus. We sought to define the specific effects of different alleles of the gene encoding adiponectin. Methods. We studied the associations of adiponectin gene sequence variations with body fat distribution and insulin indices in 503 White and 276 Black subjects of the HERITAGE Family Study cohort and subjects from a Finnish population. Results. The His111 allele frequency of the Tyr111His polymorphism in Finnish Type 2 diabetic subjects (nu200a=u200a254) was higher (5.1%) than in control subjects (nu200a=u200a270) (2.6%; Pu200a=u200a0.033). In the HERITAGE cohort, the His111 allele was associated with a lower insulin sensitivity index (Pu200a=u200a0.018) and a higher acute insulin response to glucose (Pu200a=u200a0.0098) in Whites. Other variants showed associations with adiposity and plasma lipid values only in Blacks. Among Blacks, the IVS2+G62T variant was associated with body fat (Pu200a=u200a0.002) and total cholesterol values (Pu200a=u200a0.005), and the Gly15Gly variant with cholesterol (Pu200a=u200a0.009) and triglyceride (Pu200a=u200a0.05) levels. The haplotype derived from these two polymorphisms was associated with total body fat, while the IVS2+G62T and Tyr111His–haplotype was associated with body fat and disposition index. Conclusions. The carriers of the His111 allele may have a higher risk of developing Type 2 diabetes mellitus. Racial differences were found between Blacks and Whites in body composition and lipids according to ACDC genotypes. Sequence variants in the adiponectin gene appear to be associated with diabetes and diabetes‐related phenotypes.

Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study

Objective We investigated if the differences in liver fat content would predict the development of non-fatal and fatal atherosclerotic endpoints (coronary heart disease and stroke). Design, setting and participants Our study group is a population-based, randomly recruited cohort (Oulu Project Elucidating Risk of Atherosclerosis, OPERA), initiated in 1991. The cohort consisted of 988 middle-aged Finnish participants. Intervention Total mortality and hospital events were followed up to 2009 based on the registry of the National Institute for Health and Welfare and the National death registry. Main outcome measure The severity of hepatic steatosis was measured by ultrasound and divided into three groups (0–2). Cox regression analysis was used in the statistical analysis. Results In the follow-up of years 1991–2009, 13.5% of the participants with non-fatty liver, 24.2% of participants having moderate liver fat content and 29.2% of the participants having severe fatty liver experienced a cardiovascular event during the follow-up time (p<0.001). Severe liver fat content predicted the risk for future risk of cardiovascular event even when adjusted for age, gender and study group (HR 1.92, CI 1.32 to 2.80, p<0.01). When further adjustments for smoking, alcohol consumption, low-density lipoprotein-cholesterol, body mass index and systolic blood pressure were conducted, the risk still remained statistically significant (HR 1.74, CI 1.16 to 2.63, p<0.01). Statistical significance disappeared with further adjustment for QUICKI. Conclusions Liver fat content increases the risk of future cardiovascular disease event in long-term follow-up but it is seems to be dependent on insulin sensitivity.

Estrogen replacement therapy decreases plasma adiponectin but not resistin in postmenopausal women

The effects of estrogen replacement therapy (ERT) to cardiovascular disease risk are still unclear. Low adiponectin and high resistin plasma concentrations are reported to be associated with atherosclerosis. However, it is not known how ERT affects plasma adiponectin and resistin concentrations. Seventy-three hysterectomized, nondiabetic, postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate or transdermal 17beta-estradiol gel for 6 months. Biochemical measurements were determined from samples taken before and after the therapy. Peroral estradiol valerate therapy decreased adiponectin concentrations from 13.6 to 11.6 mg/L (P = .008), whereas transdermal 17beta-estradiol gel had no effect (12.7 vs 12.2 mg/L). Neither treatment changed the resistin concentrations significantly. Plasma concentrations of estradiol and estrone did not correlate with adiponectin or resistin concentrations before or after therapy. The change in adiponectin concentration correlated significantly with the changes in waist-hip ratio, very low-density lipoprotein triglycerides, and insulin-like growth factor 1 in the peroral estradiol valerate group. The changes in these variables and the change in estradiol concentration explained 43.1% (P = .001) of the variability in the change of plasma adiponectin, the change in very low-density lipoprotein triglycerides being the strongest determinant (beta = -.407, P = .011). The results show that peroral ERT can decrease plasma adiponectin levels. However, ERT does not seem to influence plasma resistin concentrations.

Plasma adiponectin—an independent indicator of liver fat accumulation

Proinflammatory cytokines and adipokines have a significant role in the development and progression of fatty liver. The aim of our current study was to explore the major indicators for hepatic fat determined as liver brightness. In addition to peptide hormones, several known cardiovascular and metabolic risk factors were included in the model. This is a population-based, epidemiological, cross-sectional study where 1200 subjects (600 men and 600 women, aged 40-59 years) were randomly selected, half of them having hypertension and half of them being controls. The severity of liver adiposity was measured by ultrasound and based on the brightness of the liver estimated as a numerical value ranging from 0 to 2. With respect to the studied peptide hormones, the associations between liver brightness and plasma adiponectin (P < .001), leptin (P < .001), ghrelin (P = .005), and highly sensitive C-reactive protein concentrations (P < .001) were significant before adjustments. When several other risk factors (age, sex, body mass index, waist circumference, quantitative insulin sensitivity check index, smoking, and alcohol consumption) and novel risk markers (adiponectin, leptin, ghrelin, and highly sensitive C-reactive protein concentrations) were considered simultaneously, of the peptide hormones, adiponectin remained the strongest independent indicator of the brightness of the liver (P = .025). Adiponectin is a very strong predictor for liver brightness, even after adjustment for the numerous other metabolic risk factors, markers of inflammation, and novel obesity-related peptide hormones. Whether low adiponectin levels predict to liver fat accumulation remains to be explored in a future prospective follow-up of this cohort.

Metabolic syndrome in the prediction of cardiovascular events: the potential additive role of hsCRP and adiponectin

Background Highly prevalent metabolic syndrome (MS) is a major public health problem worldwide. Insulin resistance and central obesity are postulated to be the key components of this metabolic syndrome, and inflammation also plays a role in cardiovascular events. In previous years, many definitions of metabolic syndrome have emerged. Design and methods The value of MS as a predictor of cardiovascular events in median 18-year follow-up was studied in a prospective study cohort that included 1004 Finnish males and females. Cardiovascular disease included major coronary heart disease and stroke (excluding subarachnoid hemorrhage)—whichever of these happened first. Results Subjects with metabolic syndrome had a 2.01-fold (95% CI 1.46–2.77) higher probability for any cardiovascular event compared with subjects with no MS. hsCRP seemed to increase the risk prediction, whereas adiponectin was not helpful. Those having five components of MS had hazard ratios of 7.89 (2.26–27.60) for any cardiovascular event in the follow-up when compared with those having no components and adjusting by traditional risk factors (pu2009<u20090.01). Conclusions MS is an important predictor of cardiovascular events and is most harmful in combination with high plasma hsCRP. The clustering of components is especially harmful.

Adiponectin induced placental cell apoptosis could be mediated via the ADIPOR1-receptor in pre-eclampsia with IUGR.

Abstract Aims: Adiponectin and leptin are members of the adipocytokine family. Adiponectin promotes and leptin inhibits apoptosis and both are regulators of angiogenesis. Adipocytokines and their receptors are expressed in the placenta, and in the pre-eclamptic (PE) mother the serum levels of both are higher than in healthy ones. Our aim was to study the expression of adiponectin, leptin, their receptor genes and apoptosis in severely PE and normal placentas. Methods: The study group comprised 13 PE mothers and their 16 healthy controls. Placental biopsies were taken during cesarean section, the RNA was extracted and micro-array study was performed, followed by PCR and apoptosis studies. Results: The placental expression level of the leptin and adiponectin receptor 1 genes was significantly higher in PE mothers than in controls. No significant changes were observed in the levels of the adiponectin, adiponectin receptor 2 and Leptin receptor genes. The expression of the Adiponectin gene was low. The rate of apoptosis was higher in the PE placentas. Conclusions: The activity of placental adipocytokines and their receptor genes in severe PE may suggest an important role in placental angiogenesis. Placental apoptosis induced by adiponectin could be mediated via the ADIPOR1-receptor.

Plasma lipid levels and body weight altered by intrauterine growth restriction and postnatal fructose diet in adult rats

Background:Intrauterine growth restriction (IUGR) is known to affect the risk of adult diseases. Consumption of lipogenic fructose is increasing, and it is used as an enhancer of metabolic syndrome in rat experiments. The effects of IUGR, postnatal fructose diet, and their interaction on the lipid profile and adiposity were studied in adult rats.Methods:IUGR was induced by providing pregnant rats with 50% of daily food intake. From 1 mo onward, half of the offspring received a fructose-rich diet and were then followed to the age of 1 and 6 mo, when plasma lipid, glucose, and insulin levels were measured. The adipose tissue was visualized by magnetic resonance imaging at the age of 6 mo.Results:IUGR and fructose diet decreased body weight in adult rats. IUGR increased low-density lipoprotein cholesterol in 6-mo-old rats. The fructose diet evoked hypertriglyceridemia and hyperinsulinemia in both the sexes and decreased fasting glucose levels in female rats. Postnatal fructose diet increased lipid content percentage in the retroperitoneal and intra-abdominal adipose tissues in male rats. Interactions between IUGR and postnatal fructose diet were observed in adult weight in males.Conclusion:These results demonstrate the importance of IUGR and fructose diet in adverse changes in lipid and glucose metabolism.

The effect of energy restriction during pregnancy on obesity-related peptide hormones in rat offspring

It has been proposed that fetal exposure to environmental stressors, such as undernutrition, during critical periods of development may lead to adaptations that permanently change the structure and function of the body. These adaptations may be important for immediate survival during fetal development, but can predispose to disease in later life. We designed a pilot study investigating the effect of fetal undernutrition on the obesity-related peptides adiponectin, ghrelin, leptin and resistin levels in rat. We also wanted to explore changes in lipid and insulin metabolism. Sprague-Dawley rats were randomly assigned to three dietary treatment groups on day 4 of gestation. The control group was fed ad libitum and the food-restricted rats received either 75% or 50% of ad libitum food intake until parturition. Serum levels of obesity-related peptides as well as lipid and insulin levels were measured from 1-month-old pups. Serum resistin concentrations were higher in both food-restricted groups and serum adiponectin concentration was lower in the 50% food-restricted group compared to the control group. Serum total cholesterol levels were significantly higher in both food-restricted groups. These results indicate that undernutrition during fetal development may lead to unfavorable changes in obesity-related peptide hormones as well as evoking adverse changes in serum cholesterol levels. The observed changes may predispose to insulin resistance and significantly increase the risk of developing cardiovascular disease in later life.