A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

Abstract

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

Fig. 1.

Effects of losartan intracerebroventricular (ICV; 5 μg) on sympathetic nerve activity (SNA) responses to leptin (10 μg) or corticotrophin-releasing factor (CRF; 5 μg) in rats. Leptin or CRF was given 15 min after losartan or vehicle. A: changes in renal SNA in response to leptin after vehicle (n = 21) or losartan (n = 25). Renal SNA after losartan alone (n = 6) is also shown. B: changes in brown adipose tissue (BAT) SNA in response to leptin ICV (vehicle-leptin, n = 15; losartan-leptin, n = 18; and losartan-vehicle, n = 6). C: renal SNA responses to CRF in rats after 4 h (vehicle-CRF, n = 7; losartan-CRF, n = 7; and losartan-vehicle, n = 7). D and E: segments of original recordings of renal (D and E, top) and BAT SNA (D and E, bottom) at baseline and 4 h after leptin (10 μg ICV). *P < 0.05 (losartan-leptin vs. vehicle-leptin); ^†P < 0.05 (losartan-vehicle vs. vehicle-leptin). ^‡P < 0.05 (vehicle-CRF vs. losartan-vehicle); ^§P < 0.05 (losartan-CRF vs. losartan-vehicle).

Fig. 2.

Effects of ICV administration of losartan (5 μg) or vehicle on renal SNA responses to systemic administration of leptin (0.75 μg/g body wt IV; n = 5, each group). *P < 0.05 (losartan-leptin vs. vehicle-leptin); ^†P < 0.05 (losartan-vehicle vs. vehicle-leptin).

Fig. 3.

A: changes in renal SNA in response to leptin (2 μg ICV) in angiotensin II type-1a receptor knockout (AT_1aR^−/−) mice (n = 10) compared with wild-type homozygous (AT_1aR^+/+) mice (n = 14). B: changes in renal SNA in response to the melanocortin receptor agonist MTII (2 μg ICV) in AT_1aR^−/− mice (n = 12) and AT_1aR^+/+ mice (n = 18). C: BAT SNA responses to leptin (2 μg ICV) in AT_1aR^−/− (n = 7) vs. AT_1aR^+/+ mice (n = 7). D and E: segments of original recordings of the effects of leptin (2 ug ICV) on renal (D) and BAT (E) SNA in AT_1aR^+/+ and in AT_1aR^−/− mice. *P < 0.05 (AT_1aR^−/− vs. AT_1aR^+/+ mice).

Fig. 4.

Food intake (A) and body weight (B) in AT_1aR^−/− (n = 5) and AT_1aR^+/+ (n = 7) mice at baseline (day 1) and with daily ICV injections of leptin (2 μg; days 2–4). Leptin produced a significant decrease (P ≤ 0.05) in food intake and in body weight in both AT_1aR^−/− and AT_1aR^±/±, but there was no significant difference in these responses between AT_1aR^−/− and AT_1aR^±/±.

Fig. 5.

Relative expression of AT_1aR (A) and angiotensin-converting enzyme (ACE; B) mRNA in arcuate nucleus, paraventricular nucleus (PVN), and subfornical organ (SFO) of Sprague-Dawley rats 4 h after ICV injection of leptin (10 μg) or vehicle (n = 6 each group). *P ≤ 0.05 (vehicle vs. leptin).

Fig. 6.

A: changes in mean arterial pressure (MAP) after intravenous administration of angiotensin I (ANG I; 50 ng; n = 4) or ANG II (50 ng; n = 4) at baseline and for 15 to 300 min after captopril (12.5 μg ICV) in rats. Effects of captopril (12.5 μg ICV) on renal (B) and BAT (C) SNA responses to leptin (10 μg ICV) in rats (n = 6 each group). D: renal SNA responses to CRF in rats after captopril (12.5 μg ICV: after 4 h, n = 6 each group). ^‡P < 0.05 (vs. baseline); *P < 0.05 (vehicle-leptin vs. captopril-leptin); ^†P < 0.05 (vehicle-leptin vs. captopril-vehicle); ^§P < 0.05 (captopril-leptin vs. captopril-vehicle). For D: *P < 0.05 (vehicle-CRF vs. captopril-vehicle); ^§P < 0.05 (captopril-CRF vs. captopril-vehicle).