Pilot studies to demonstrate that intestinal mucosal afferent nerves are functionally linked to visceral adipose tissue.

Dietary capsaicin reduces rodent visceral fat weight. We tested the hypothesis that intact intestinal mucosal afferent nerve function is necessary for fat deposition in visceral adipose tissue sites. Rats were treated daily for 2 weeks with intragastric (chronic treatment) vehicle or capsaicin. Superior mesenteric artery blood flow and mesenteric and inguinal fat blood flow were measured before and after capsaicin was administered into the duodenum (acute treatment). Fat from all sites was dissected and weighed. Chronic capsaicin significantly attenuated acute capsaicin-induced mesenteric hyperemia but did not abolish the reflex wiping of the eye exposed to capsaicin, indicating that functional ablation was limited to the intestinal mucosal afferent nerves. The associated vasoconstriction in adipose tissue was inhibited at the visceral (mesenteric) site and maintained but attenuated at the subcutaneous (inguinal) site. The onset of vasoconstriction was instantaneous, indicating a reflex mechanism. There was a redistribution of fat from visceral to subcutaneous sites, reflected by a decrease and an increase in the percentage of body fat in the visceral and subcutaneous sites, respectively. These pilot studies reveal for the first time that normal intestinal mucosal afferent nerve function is necessary for the physiologic accumulation of fat in visceral adipose tissue sites.

Insulin stimulates endogenous angiotensin II production via a mitogen-activated protein kinase pathway in vascular smooth muscle cells.

OBJECTIVE: The present study was designed to determine the effects of insulin on cytosolic angiotensin II production and proliferation in cultured rat vascular smooth muscle cells. DESIGN AND METHODS: Vascular smooth muscle cells were incubated with insulin for 48 h. Cytosolic angiotensin I and II were determined by radioimmunoassays of purified cell homogenates. Angiotensin II was also detected by immunohistochemistry of intact cells. Cell proliferation was determined by pulse labeling with radiolabeled thymidine. Angiotensinogen mRNA expression was determined by slot-blot analysis. RESULTS: Insulin significantly increased cytosolic angiotensin II concentration in vascular smooth muscle cells. Lisinopril, omapatrilat and irbesartan inhibited this increase of angiotensin II, but had no effect on angiotensin I levels. Immunohistochemical staining confirmed the presence of angiotensin II in control and insulin-treated vascular smooth muscle cells. Insulin increased cell proliferation, and addition of lisinopril, omapatrilat or irbesartan inhibited this effect. Insulin also increased expression of angiotensinogen mRNA in cultured vascular smooth muscle cells, but PD98059, a mitogen-activated protein kinase inhibitor, prevented the rise in angiotensinogen expression. CONCLUSION: These results support the concept that insulin stimulates angiotensin II production in cultured vascular smooth muscle cells through a mitogen-activated, protein kinase-dependent pathway that might be a factor in the progression of atherosclerosis. Agents that block the renin-angiotensin system have direct protective effects, reducing vascular angiotensin II and growth of vascular smooth muscle cells and are thus of cardiovascular benefit.