The present study evaluated the effects of a high-fat diet on the expression of adiponectin and adiponectin receptors in rats. These rats did not become obese during the study because the percentage of fat in their diet and the period of diet treatment were not great enough to alter the body weight gain or the carcass lipid content compared to the group fed normal chow. Therefore, we can be sure that our results were restricted to the effects of the diet and were not due to metabolism changes induced by obesity.
Some studies show that adiponectin plays a role in the reduction of insulin sensitivity caused by high-fat diet [39
]. Our results showed that 21 days of a high-fat diet containing 20% fat was not enough to modify insulin serum concentrations although there was an increase in glycemia. We demonstrated that hyperglycemia promoted by the high-fat diet was accompanied by a reduction in adiponectin gene expression in the SUB adipose tissue, but did not lead to a decrease in serum adiponectin levels, suggesting that there is a compensatory effect of the other fat depots on serum adiponectin levels. These results demonstrate the complexity of post-transcriptional mechanisms regulating adiponectin mRNA. The isolated effect of the high-fat diet on the SUB adipose tissue may be due to the fact that adiponectin gene and protein levels are higher in SUB adipose tissue than in other adipose depots [41
Previous studies have suggested that increased insulin levels due to a high-fat diet may affect expression of the adiponectin receptors [18
]. This insulin regulatory effect on adiponectin receptor expression is controversial because it has been shown that insulin represses the expression of both adiponectin receptors in muscle and liver [43
], that adipoR1, but not adipoR2, is repressed by insulin [45
], that there is no difference in adipoR1 expression in the muscles of human diabetics compared to non-diabetics [46
] and, similar to our results, that insulin increases adipoR1 expression in muscle [48
]. In our study, we also demonstrated that there was a decrease in adipoR1 protein expression in the RET adipose tissue. However, because the insulin levels in our HF group and C group were similar, we can assume that the alterations in the expression of adiponectin receptors were not due to insulin. Free fatty acid levels have also been found to upregulate adiponectin receptor expression [46
Some previous studies have shown that diet-induced obesity is associated with insulin resistance in liver and muscle, but not in adipose tissue [50
]. However, in the present study, we demonstrated that adipoR1 protein expression increased in muscle and adipoR2 gene expression increased in muscle and liver after 3 weeks of HF diet, suggesting that this may be a compensatory mechanism that acts to protect an organism from insulin resistance induced by HF diet because it has been well documented that adiponectin expression in muscle promotes an increase in insulin sensitivity [52
]. Similar results were found in a study by Barnea et al [49
] in which HF diet enhanced adipoR1 and adipoR2 expression in the muscles of mice fed with a 22% soybean fat diet for 4 months.
Peng et al [54
] have proposed that adiponectin signaling may be a crosslink between HF diet, hepatic inflammation and nonalcoholic fatty liver disease. In fact, they found that HF diet-induced liver steatosis was associated with a reduction in serum adiponectin levels and downregulation of adipoR2 expression in the liver. We found that adipoR2 gene expression was increased in the livers of the HF group of rats. A similar result was found by Bullen et al [18
] in mice fed a high-fat diet. These results indicate that other factors may play a role in the regulation of the adiponectin receptors in the liver.
The stimulation of adrenal glucocorticoid secretion by HF diet has been described in animals and humans [55
]. Accordingly, Wohlers et al [21
] showed that feeding rats for 7 weeks with a HF diet that was supplemented with soybean oil or fish oil (15% fat) resulted in increased serum corticosterone levels compared to those in rats fed a control diet (4% fat). Our animals fed with a soybean oil HF diet (15% fat) for only 3 weeks did not increase the serum levels of corticosterone compared to those of the control group. After 3 weeks of HF diet treatment, Drake et al [57
] observed an increase in glucocorticoid clearance by hepatic A-ring reductase. The authors of this study suggested that this mechanism could protect against the metabolic complications of obesity induced by HF diet.
In HF diet-treated rats, 72 h after adrenalectomy, glycemia and insulin levels were similar to the S-ADREC group. However, glucocorticoid therapy via dexamethasone treatment in adrenalectomized rats promoted hyperglycemia and hyperinsulinemia. This treatment also decreased adiponectin serum concentrations, which was accompanied by a decrease in adiponectin mRNA in EPI adipose tissue, demonstrating that the excess of glucocorticoids rather than the glucocorticoids themselves per se
influence adiponectin, glucose and insulin serum concentrations. Chronic treatment with glucocorticoids may result in insulin resistance followed by hyperinsulinemia and hyperglycemia [58
]. These alterations of insulin and glucose levels can be partially explained by a decrease in insulin-dependent glucose uptake and an increase in liver gluconeogenesis. Another potential explanation could be the decrease in adiponectin serum levels observed in the present study. Adrenalectomy may increase adiponectin gene expression in SUB adipose tissue even when combined with HF diet treatment because HF diet alone was able to reduce adiponectin gene expression. With regard to expression of the adiponectin receptors in SUB adipose tissue, adrenalectomy increased adipoR1 and adipoR2 protein levels, and the dexamethasone therapy reversed these effects. AdipoR2 protein expression in muscle was reduced by adrenalectomy, but, upon the addition of glucocorticoid therapy, the adipoR2 mRNA levels did not reach the normal mRNA levels observed in the sham group. This reduction in adipoR2 expression may be due to other hormones secreted by the adrenal glands, such as mineralocorticoids and catecholamines, and, for this reason, the treatment with dexamethasone was not able to reverse the adipoR2 reduction. Furuhashi et al [61
] observed that rennin-angiotensin-aldosterone system blockade increases serum adiponectin concentrations with improvement in insulin sensitivity in patients with hypertension. To our knowledge, no direct effects of aldosterone on adiponectin and adiponectin receptors were observed despite the fact that both adiponectin receptors, adipoR1 and adipoR2, have been showed to be expressed in mouse adrenal gland and adrenocortical Y-1 cells [62
] and in human adrenal cortex and aldosterone-producing adenoma tissue [63
]. Few studies showed that exogenous administration of dehydroepiandrosterone (DHEA) upregulated adiponectin expression and secretion from adipose tissue of rats [64
]. Some studies have analyzed the effects of catecholamines on the regulation of adiponectin and adiponectin receptor gene and protein expression. Catecholamines inhibit adiponectin mRNA expression in 3T3-L1 adipocytes [66
] and adipoR1 and adipoR2 expression in cultured cardiomyocytes [67
]. In addition, Iwen et al [68
] recently showed that an increase in sympathetic nervous activity caused a decrease in plasma adiponectin levels in humans. Oana et al [10
] showed that the β3-adrenoceptor agonist CL-316 increased plasma adiponectin levels and the expression of adiponectin mRNA in the EPI white adipose tissue of db/db
mice. Another study by Fu et al [69
] demonstrated that treatment of 3T3-L1 adipocytes with the β-adrenoceptor agonist isoproterenol increased expression of the adipoR2, but not the adipoR1 receptor. These results are in accordance with the findings of the present study related to the effects observed in the A-DEXA group. However, more studies are needed to better understand the effects of catecholamines on the regulation of the adiponectin system because some diseases associated with obesity are related to sympathetic nervous system activity.