Selective leptin resistance revisited

Abstract

In addition to effects on appetite and metabolism, leptin influences many neuroendocrine and physiological systems, including the sympathetic nervous system. Building on my Carl Ludwig Lecture of the American Physiological Society, I review the sympathetic and cardiovascular actions of leptin. The review focuses on a critical analysis of the concept of selective leptin resistance (SLR) and the role of leptin in the pathogenesis of obesity-induced hypertension in both experimental animals and humans. We introduced the concept of SLR in 2002 to explain how leptin might increase blood pressure (BP) in obese states, such as diet-induced obesity (DIO), that are accompanied by partial leptin resistance. This concept, analogous to selective insulin resistance in the metabolic syndrome, holds that in several genetic and acquired models of obesity, there is preservation of the renal sympathetic and pressor actions of leptin despite attenuation of the appetite and weight-reducing actions. Two potential overlapping mechanisms of SLR are reviewed: 1) differential leptin molecular signaling pathways that mediate selective as opposed to universal leptin action and 2) brain site-specific leptin action and resistance. Although the phenomenon of SLR in DIO has so far focused on preservation of sympathetic and BP actions of leptin, consideration should be given to the possibility that this concept may extend to preservation of other actions of leptin. Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension.

Keywords: adipose tissue; blood pressure; renal; renin-angiotensin system; sympathetic.

Fig. 1.

Left: data for mean arterial pressure (MAP) in wild-type vs. obese, leptin-deficient ob/ob mice (81). Right: systolic arterial pressure (AP) in wild-type vs. skinny, hyperleptinemic transgenic mice overexpressing leptin from a liver promoter (1). Obese leptin-deficient mice had lower AP than wild-type controls, whereas skinny hyperleptinemic mice had higher AP than wild-type controls. Tg, transgenic. *P < 0.05. [Adapted from Aizawa-Abe et al. (1) and Mark et al. (81).].

Fig. 2.

Changes in MAP (top) and renal sympathetic nerve activity (SNA; bottom) in diet-induced obese hypertensive rabbits after cerebroventricular administration of vehicle, a leptin antagonist, or an insulin antagonist (76). The leptin antagonist produced significant (***P < 0.001) decreases in MAP and renal SNA, whereas the insulin antagonist produced a smaller decrease in MAP (*P < 0.05) and did not decrease renal SNA.

Fig. 3.

Schematic diagram depicting the concept of selective leptin resistance.

Fig. 4.

Evidence that selective leptin resistance (SLR) contributes to obesity-induced hypertension in mouse models of Bardet-Biedl syndrome (Bbs) (121). A: recordings of renal SNA at baseline and 4 h after cerebroventricular administration of leptin, 5 μg in Bbs 2, Bbs 4, and Bbs 6 knockout and in wild-type mice. Compared with wild-type mice, Bbs 4 and Bbs 6 knockout mice had elevated baseline renal SNA and preserved renal SNA responses to leptin. Bbs 2 knockout mice had normal baseline renal SNA and loss of renal SNA responses to leptin. B: baseline values for mean arterial pressure in the wild-type and Bbs 2, Bbs 4, and Bbs 6 knockout mice. Bbs 2 knockout mice were normotensive, whereas Bbs 4 and Bbs 6 knockouts were hypertensive.

Fig. 5.

Schematic diagram depicting several leptin-STAT3 and leptin-PI3K-mediated actions with emphasis on the differential regional SNA actions. STAT3 mediates increases in brown adipose tissue (BAT) SNA, whereas PI3K increases white adipose tissue (WAT) SNA but not BAT SNA. PI3K mediates leptin-induced increases in renal SNA, whereas STAT3 does not. Nevertheless, both STAT3 and PI3K mediate leptin-induced increases in blood pressure.

Fig. 6.

Recordings of renal and BAT SNA at baseline and 5 to 6 h after microinjection of leptin, 0.5 μg, into the arcuate nucleus or caudal nucleus tractus solitarii (cNTS) in Sprague-Dawley rats. A: arcuate injection of leptin increased SNA to both kidney and BAT (120) [Adapted from Rahmouni and Morgan (120)]. B: in contrast, cNTS injection of leptin increased SNA to kidney but not to BAT (84).

Fig. 7.

Top: changes in renal SNA in Sprague-Dawley rats after cerebroventricular administration of leptin (vehicle-leptin), losartan (losartan-vehicle), or leptin following losartan (losartan-leptin). Leptin alone increased renal SNA. Losartan blocked leptin-induced increases in renal SNA. Losartan alone had no significant effect on renal SNA. As depicted in the schematic (lower panel), these studies suggest that brain AT₁R mediate the renal SNA responses to leptin (62).