Stimulatory Effect of Leptin on Nitric Oxide Production Is Impaired in Dietary‐Induced Obesity

Abstract

BELTOWSKI, JERZY, GRAŻ YNA WÓ JCICKA, AND ANNA JAMROZ. Stimulatory effect of leptin of nitric oxide production is impaired in dietary-induced obesity. Obes Res. 2003;11:1571-1580. Objective: We investigated the effect of leptin on nitric oxide production in lean and rats made obese by a highcalorie diet. Research Methods and Procedures:The animals were placed in metabolic cages, and urine was collected in 2-hour periods after leptin (1 mg/kg intraperintoneally) or vehicle administration. Blood was obtained 0.5, 1, 2, 4, or 6 hours after injection. Results: Leptin had no effect on systolic blood pressure in either lean or obese animals. Plasma concentration of NO metabolites (nitrites ϩ nitrates, NO x ) increased in lean rats by 31.5%, 58.0%, and 27.9% at 1, 2, and 4 hours after leptin injection, respectively. In the obese group, plasma NO x increased only at 2 hours (ϩ36.5%). Leptin increased urinary NO x excretion by 31.8% in the first 2-hour period after injection in lean but not in obese rats. In lean animals, leptin elevated plasma cyclic 3Ј,5Ј-guanosine monophosphate (cGMP) at 1, 2, and 4 hours by 35.3%, 96.3%, and 57.3%, respectively. In the obese group, plasma cGMP was higher only at 2 and 4 hours (ϩ44.6% and ϩ32.1%, respectively). Urinary excretion of cGMP increased in lean animals by 67.1% in the first period and by 50.4% in the second period. In the obese group, leptin induced a 53.9% increase in urinary cGMP excretion only in the first 2-hour period. Discussion: The stimulatory effect of leptin on NO production is impaired in dietary-induced obesity; however, leptin does not increase blood pressure in obese animals, suggesting that other NO-independent depressor mechanisms are stimulated.

Role of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in the regulation of blood pressure by leptin in lean and obese rats

“…In the remaining animals obesity was induced by feeding them highcalorie "cafeteria diet" for either 1 or 3 months. High-calorie diet consisted of standard chow combined 1:1 (wt/wt) with a liquid diet containing equal amounts (grams) of sucrose, glucose, whole milk powder and soybean powder suspended in tap water (Bełtowski et al, 2003). The composition of this diet was similar to standard chow (66% carbohydrates, 20% protein, and 14% fat).…”

“…Second, leptin-induced vasodilation in human coronary (Matsuda et al, 2003) and forearm (Nakagawa et al, 2002) circulation was not affected by NOS blockade. Third, in experimentally induced obesity leptin does not elevate blood pressure despite impaired effect on NO production, suggesting that other hypotensive mechanisms compensate for NO deficiency (Bełtowski et al, 2003). The mechanism of NOindependent vasodilatory effect of leptin is, however, unclear.…”

Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity

“…To explain this, recent studies have demonstrated the impairment of leptin's metabolic effects and leptin-induced NO production, i.e. "leptin resistance", in obesity (Beltowski et al 2003;Rahmouni et al 2005) and human hypertension (Tsuda and Nishio 2004). Leptin resistance may be caused by inflammatory mechanisms, as CRP impairs intracellular leptin signaling (Correia et al 2002;Chen et al 2006).…”

A Positive Association between Leptin and Blood Pressure of Normal Range in Japanese Men

“…Second, although the primary effect of leptin on blood pressure may be the central stimulation of sympathetic nerve activity ( 24 ), other studies have suggested that leptin may have another, contradictory effect on blood pressure-i.e. , a vasodilative action that may or may not be related to a release of nitric oxide from the vascular endothelium ( 25 -27 ), and the stimulatory effect of leptin on nitric oxide was possibly modified by the degree of obesity ( 28 ).…”