In the present study, we revealed that candesartan ameliorated not only hypertension but also lipoatrophy in SHRSP. One of the mechanisms of decreasing of blood pressure and lowering of stroke lesion may be due to improvement of adipocyte dysfunction.
Although angiotensin II was reported to inhibit adipocyte differentiation [14, 15], angiotensin II-induced lipolysis was ameliorated by the ARB losartan . The angiotensin II type 1 and type 2 receptors are involved in determining adipocyte size [8, 17]. Thus, the RAS in adipose tissue is closely related to adipocyte growth and function. Accordingly, angiotensin II signaling via the type 1 and type 2 receptors may regulate adipocyte particle size, and ARBs may ameliorate adipocyte dysfunction.
In this study, plasma leptin levels were higher in the candesartan group than in the control group, but adiponectin levels were similar in both groups. However, the mRNA expression levels of leptin, adiponectin, and PPARγ were higher in the candesartan group than in the control group.
Leptin is secreted from hypertrophic adipocytes and its circulating level is directly proportional to body fat. In terms of its roles, leptin stimulates energy consumption by activating the sympathetic nerve system and promotes fatty acid β-oxidation in peripheral tissues . Plasma leptin and epididymal leptin mRNA levels were higher in the candesartan group than in the control group. This increase in leptin expression possibly contributed to the lower incidence of stroke in the candesartan-treated group. Although precise mechanisms are still unknown, leptin may protects against severe energy depletion due to lopatrophy in SHRSP. This possibility is supported by a study conducted by Avraham et al. , who reported that leptin administration significantly improved neurological disability and reduced infarct volume following permanent middle cerebral artery occlusion in Sebra mice. Furthermore, in clinical trials, it was reported that leptin improved insulin resistance in lipoatrophic patients [20, 21]. Although further large-scale trials are needed to demonstrate the long-term efficacy and safety of leptin, a new drug application for leptin is anticipated . To explore the therapeutic role of leptin, Ebihara et al.  crossed A-ZIP/F1 mice, which exhibit severe lipoatrophy, with mice overexpressing leptin in the liver. The resulting doubly transgenic mice virtually lacked adipose tissue but had elevated leptin levels. These mice showed improvements in insulin sensitivity, hepatic steatosis, and normal glucose and insulin levels . These results indicate that leptin has an important role in the pathogenesis of circulatory disturbance as well as metabolic disorders.
On the other hand, the mRNA expression levels of adiponectin and PPARγ were also increased in the candesartan-treated group. PPARγ is nuclear transcription factor in adipocytes, where it control the expression of numerous genes involved in glucose and lipid metabolism, and cell differentiation in particular . Zorad et al.  investigated the effects of candesartan in normotensive WKY and reported marked decreases in body weight with increasing of expression of adiponectin and PPARγ. However, the plasma leptin level and its mRNA expression in adipose tissue were lower in the candesartan group than in the control group. Their findings were generally similar to those of our present study, except for leptin expression. This difference may be due to differences in methods, including strain of rat, candesartan dose, and the duration of treatment. Nevertheless, the results of both studies are consistent in terms of the improvement in adipocyte function in candesartan-treated rats.
As described above, candesartan ameliorated adipocyte dysfunction in SHRSP, which we thought were mediated by an increase in adiponectin production. To confirm this hypothesis, we investigated the effects of continuous intravenous infusion of recombinant adiponectin in mature SHRSP. The results of this experiment revealed an increase in plasma adiponectin levels, although the increase was not statistically significant. However, the adiponectin mRNA expression level in adipose tissue was significantly higher in the adiponectin-treated group than in the control group. On the other hand, there were no significant differences in the mRNA expression levels of leptin, Adipo-R1, AdipoR-2, or cadherin 13 between the two groups. Unexpectedly, we found no differences in body weight or blood pressure between the two groups. Bassi et al.  investigated the chronic effects of centrally administered adiponectin in SHR and reported that adiponectin did not appear to have an important role in long-term control of blood pressure. Thus, we and Bassi et al.  found no remarkable effects of adiponectin on the circulatory disturbances in SHR or SHRSP. This means that adiponectin is not a major regulator of blood pressure in essential (i.e., genetic) hypertension. However, several reports have indicated that adiponectin may lower blood pressure by regulating the nitric oxide synthetic pathway [26, 27]. We did not investigate the changes in nitric oxide-related molecules in the present study.
In conclusion, we revealed the candesartan has beneficial effects not only for decreasing of blood pressure but also improvement of adipocyte dysfunction, although the latter must be secondary to decreasing of blood pressure. Leptin may be more deeply related to decreasing of stroke as compared to adiponectin in SHRSP. Further studies are required to elucidate t role of renin-angiotensin system in adipocyte in relation to hypertension and stroke.