Selective leptin resistance revisited.

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.

Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation.

RATIONALE: The hypothalamic arcuate nucleus (ARC) is considered a major site for leptin signaling that regulates several physiological processes. OBJECTIVE: To test the hypothesis that leptin receptor in the ARC is required to mediate leptin-induced sympathetic activation. METHODS AND RESULTS: First, we used the ROSA Cre-reporter mice to establish the feasibility of driving Cre expression in the ARC in a controlled manner with bilateral microinjection of adenovirus-expressing Cre-recombinase (Ad-Cre). Ad-Cre microinjection into the ARC of ObR(flox/flox) mice robustly reduced ObR expression and leptin-induced Stat3 activation in the ARC but not in the adjacent nuclei, confirming the efficacy and selectivity of the ARC deletion of ObR. Critically, deletion of ObR in the ARC attenuated brown adipose tissue and renal sympathetic nerve responses to leptin. We also examined whether ObR in the ARC is required for the preserved leptin-induced increase in renal sympathetic activity in dietary obesity. We found that deletion of ARC ObR abrogated leptin-induced increases in renal sympathetic discharge and resolved arterial pressure elevation in diet-induced obese ObR(flox/flox) mice. CONCLUSIONS: These data demonstrate a critical role for ObR in the ARC in mediating the sympathetic nerve responses to leptin and in the adverse sympathoexcitatory effects of leptin in obesity.

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

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.

Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin.

The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.

Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating ß3-adrenergic mechanisms.

A role for oxidative stress in the brain has been suggested in the pathogenesis of diet-induced obesity (DIO), although the underlying neural regions and mechanisms remain incompletely defined. We tested the hypothesis that NADPH oxidase-dependent oxidative stress in the paraventricular nucleus (PVN), a hypothalamic energy homeostasis center, contributes to the development of DIO. Cre/LoxP technology was coupled with selective PVN adenoviral microinjection to ablate p22phox , the obligatory subunit for NADPH oxidase activity, in mice harboring a conditional p22phox allele. Selective deletion of p22phox in the PVN protected mice from high-fat DIO independent of changes in food intake or locomotor activity. This was accompanied by ß3-adrenoceptor-dependent increases in energy expenditure, elevations in brown adipose tissue thermogenesis, and browning of white adipose tissue. These data reveal a potentially novel role for brain oxidative stress in the development of DIO by modulating ß3-adrenoceptor mechanisms and point to the PVN as an underlying neural site.

Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain.

Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress - which is emerging as a key contributor to a number of chronic diseases including obesity - in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular subfornical organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose-regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.

Role of selective leptin resistance in diet-induced obesity hypertension.

Leptin is an adipocyte-derived hormone that plays a key role in the regulation of body weight through its actions on appetite and metabolism. Leptin also increases sympathetic nerve activity (SNA) and blood pressure. We tested the hypothesis that diet-induced obesity is associated with resistance to the metabolic actions of leptin but preservation of its renal SNA and arterial pressure effects, leading to hypertension. Mice were fed a high-fat diet for 10 weeks to induce moderate obesity. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular leptin was significantly attenuated in the obese mice. Regional SNA responses to leptin were differentially altered in diet-induced obese mice. Renal SNA response to leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated in obese mice. Radiotelemetric arterial pressure was approximately 10 mmHg higher in obese mice. Furthermore, the increase in arterial pressure in response to long-term (12 days) leptin treatment was preserved in obese mice. Thus, mice with diet-induced obesity exhibit circulating hyperleptinemia and resistance to the metabolic actions of leptin. However, there is preservation of the renal sympathetic and arterial pressure responses to leptin, which represent a potential mechanism for the adverse cardiovascular consequences of obesity.

Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin.

Central melanocortin signaling plays an important role in regulation of energy homeostasis by leptin and insulin. We investigated the interaction between leptin, insulin, and melanocortin-4 receptors (MC-4Rs) in the control of renal sympathetic nerve activity (RSNA) in mice. We compared the effects of intracerebroventricular (ICV) administration of leptin, insulin, MC-3/4R agonist (MTII), and corticotrophin-releasing factor (CRF) on RSNA in leptin receptor-deficient (db/db) mice, MC-4R knock-out mice, and their wild-type controls. ICV administration of leptin and MTII caused a significant and dose-dependent increase in RSNA in control mice. As expected, leptin had no significant effect on RSNA in the db/db mice. Interestingly, db/db mice exhibited markedly attenuated RSNA responses to ICV administration of MTII. However, the increase in RSNA induced by insulin and CRF was comparable between db/db and control mice. In the heterozygous and homozygous MC-4R knock-out mice, the RSNA response to MTII was attenuated and abolished, respectively. The RSNA response to ICV leptin and insulin was also attenuated and abolished in the heterozygous and homozygous MC-4R knock-out mice, respectively. In contrast, CRF induced a similar increase in RSNA in the MC-4R knock-out and wild-type mice. Our data demonstrate that in the absence of leptin receptors, the sympathoexcitatory effects of melanocortin system stimulation are attenuated. In addition, the renal sympathoexcitatory responses to leptin and insulin are dependent on the MC-4R, demonstrating an important role for the MC-4R in the regulation of renal sympathetic nerve outflow by leptin and insulin.

Leptin potentiates thermogenic sympathetic responses to hypothermia: a receptor-mediated effect.

Leptin contributes to the regulation of thermogenesis. In rodents, sympathetic nerve activity efferent to interscapular brown adipose tissue (IBAT-SNA) is involved. On the basis of the hypotheses that 1) leptin acutely potentiates hypothermia-induced increases in IBAT-SNA; 2) this action of leptin is specific to IBAT-SNA, i.e., it does not occur with renal sympathetic nerve activity (R-SNA); and 3) this effect of leptin depends on intact and functional leptin receptors, we measured IBAT-SNA and R-SNA in anesthetized lean and diet-induced obese Sprague-Dawley and in obese Zucker rats, randomly assigned to low-dose leptin or vehicle. Before the start of leptin or vehicle and 5 min, 90 min, and 180 min after, hypothermia (30 degrees C) was induced. Compared with vehicle, leptin did not significantly alter baseline R-SNA or IBAT-SNA. In lean Sprague-Dawley rats, hypothermia-induced increases in IBAT-SNA were significantly augmented by leptin but not by vehicle. In obese Sprague-Dawley rats, leptin did not potentiate hypothermia-induced increases in IBAT-SNA. In Zucker rats, IBAT-SNA did not increase with hypothermia and leptin was not able to induce sympathoactivation with cooling. Changes in R-SNA during hypothermia were not significantly modified by leptin in either group. Thus, low-dose leptin, although not altering baseline SNA, acutely enhances hypothermia-induced sympathetic outflow to IBAT in lean rats. This effect is specific for thermogenic SNA because leptin does not significantly alter the response of R-SNA to hypothermia. The effect depends on intact and functional leptin receptors because it occurs neither in rats with a leptin receptor defect nor in rats with acquired leptin resistance.

The concept of selective leptin resistance: evidence from agouti yellow obese mice.

Leptin, a hormone secreted by adipose tissue, acts to inhibit appetite and promote metabolism, thereby reducing body weight. Leptin also increases sympathetic activity and arterial pressure. Several murine models of obesity, including agouti obese mice, exhibit resistance to the anorexic and weight-reducing effects of leptin. Hypertension in agouti mice has been attributed to hyperleptinemia. These observations pose a seeming paradox. If these mice are leptin-resistant, then how can leptin contribute to hypertension? We tested the novel hypothesis that these mice have selective leptin resistance, with preservation of the sympathoexcitatory action despite resistance to the weight-reducing actions. Leptin-induced decreases in food intake and body weight were less in agouti obese mice than in lean littermates. In contrast, leptin-induced increases in sympathetic nerve activity did not differ in obese and lean mice. These findings support the concept of selective leptin resistance, with resistance to the metabolic actions of leptin but preservation of the sympathoexcitatory actions. This finding may have potential implications for human obesity, which is associated with elevated plasma leptin and is thought to be a leptin-resistant state. If leptin resistance is selective in obese humans, then leptin could contribute to sympathetic overactivity and its adverse consequences in human obesity.

Angiotensin type 1a receptors in the forebrain subfornical organ facilitate leptin-induced weight loss through brown adipose tissue thermogenesis.

OBJECTIVE: Elevations in brain angiotensin-II cause increased energy expenditure and a lean phenotype. Interestingly, the metabolic effects of increased brain angiotensin-II mimic the actions of leptin, suggesting an interaction between the two systems. Here we demonstrate that angiotensin-type 1a receptors (AT1aR) in the subfornical organ (SFO), a forebrain structure emerging as an integrative metabolic center, play a key role in the body weight-reducing effects of leptin via brown adipose tissue (BAT) thermogenesis. METHODS: Cre/LoxP technology coupled with targeted viral delivery to the SFO in a mouse line bearing a conditional allele of the Agtr1a gene was utilized to determine the interaction between leptin and SFO AT1aR in metabolic regulation. RESULTS: Selective deletion of AT1aR in the SFO attenuated leptin-induced weight loss independent of changes in food intake or locomotor activity. This was associated with diminished leptin-induced increases in core body temperature, blunted upregulation of BAT thermogenic markers, and abolishment of leptin-mediated sympathetic activation to BAT. CONCLUSIONS: These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.

Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications.

Leptin, an adipocyte secreted hormone, acts in the hypothalamus to inhibit appetite and promote thermogenic metabolism, thereby reducing adiposity and body weight. Leptin has multiple autonomic and cardiovascular actions, including sympathetic activation, increases in endothelium derived nitric oxide (NO), and angiogenesis. The predominant cardiovascular effect of chronic hyperleptinemia is a pressor effect mediated by increased sympathetic activity. The sympathetic and cardiovascular actions of leptin are discussed and evidence derived from studies of obese mice for the novel concept of selective leptin resistance is reviewed. This concept holds that in some obese states, there is preservation of the sympathoexcitatory actions of leptin despite resistance to the satiety and weight-reducing actions of the hormone. Selective leptin resistance might explain how hyperleptinemia could contribute to increases in sympathetic activity and arterial pressure in obese states where there is resistance to the metabolic (satiety and weight-reducing) actions of leptin. It is speculated here, that this concept may have potential implications for human obesity, which is often associated with elevated plasma leptin and partial resistance to the satiety effects of leptin. If selective leptin resistance occurs in obese humans, then leptin could contribute to the sympathetic overactivity and hypertension despite resistance to its metabolic actions.

Differential modulation of leptin-induced sympathoexcitation by baroreflex activation.

OBJECTIVE: Leptin induces increases in sympathetic nerve activity to various regions. This has implications for energy balance, thermogenesis and possibly cardiovascular regulation. The aim of the present study was to test the hypothesis that the increases in sympathetic nerve activity induced by leptin in different regions respond differentially to baroreflex activation. METHODS: A total of 24 anesthetized male Sprague-Dawley rats were assigned to either leptin (0.5 mg/kg body weight bolus i.v., followed by 0.5 mg/kg body weight i.v. during 3 h, n = 12) or vehicle (n = 12) treatment. Mean arterial pressure (MAP), heart rate (HR), interscapular brown adipose tissue sympathetic nerve activity (IBAT-SNA) and renal sympathetic nerve activity (RSNA) were recorded continuously. Before and 3 h after start of leptin or vehicle, baroreceptor activity was decreased by lowering MAP with nitroprusside and increased by raising MAP with phenylephrine. RESULTS: Compared with vehicle, leptin significantly increased IBAT-SNA (294 +/- 78%) and RSNA (211 +/- 28%), while not altering MAP (117 +/- 5 versus 118 +/- 4 mmHg). Baroreflex activation by phenylephrine completely suppressed the leptin-induced increase in RSNA. In contrast, the leptin-induced increase in IBAT-SNA could not be overridden by baroreflex activation. Compared with vehicle, leptin did not significantly alter the maximum gain of the RSNA-MAP (-3.8 +/- 0.7 versus -2.7 +/- 0.3% of maximum mmHg-1, NS) or the IBAT-SNA-MAP curves (-1.9 +/- 0.7 versus -1.4 +/- 0.3% of maximum mmHg-1, NS). CONCLUSIONS: Leptin-induced regional increases in sympathetic nerve activity respond non-uniformally to baroreflex activation. The increase in RSNA can be suppressed by baroreflex activation, suggesting that the leptin-induced increase in RSNA subserves circulatory functions. In contrast, the increase in IBAT-SNA with leptin is not prevented by baroreflex activation, suggesting the recruitment of sympathetic fibers that serve thermogenic or metabolic and not circulatory functions.

Hemodynamic consequences of neuropeptide Y-induced obesity.

BACKGROUND: Acute central nervous system administration of neuropeptide Y (NPY) elicits variable hemodynamic responses. Chronic intracerebroventricular (ICV) administration of NPY produces obesity in rats. Obesity has been shown to increase arterial pressure. METHODS: In this study we examined the chronic hemodynamic effects of NPY-induced obesity. Sprague-Dawley rats were implanted with radiotelemetry transmitters to continuously record heart rate and arterial pressure in the conscious state. Neuropeptide Y or vehicle was delivered into the third cerebral ventricle by osmotic minipumps over 2 weeks. Three groups were studied: vehicle, NPY-treated (free-fed), and NPY-treated (pair-fed to vehicle-treated rats). RESULTS: Neuropeptide Y increased food intake and body weight in free-fed animals, and substantially augmented visceral adiposity in both free- and pair-fed rats. Despite increased adiposity, chronic ICV administration of NPY in conscious unstressed rats did not increase arterial pressure. Neuropeptide Y decreased heart rate, suggesting a sympathoinhibitory effect. CONCLUSIONS: Obesity induced by 2-week ICV administration of NPY does not increase arterial pressure, perhaps indicating inhibition of sympathetic outflow that may oppose the pressor effect of adiposity.

The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects.

The adipocyte-derived hormone leptin acts within the central nervous system to decrease food intake and body weight and to increase renal and thermogenic brown adipose tissue sympathetic nerve activity (SNA). Previous studies have focused on hypothalamic brain regions, although recent findings have identified leptin receptors (ObR) in a distributed brain network, including the circumventricular subfornical organ (SFO), a forebrain region devoid of a blood-brain barrier. We tested the hypothesis that ObR in the SFO are functionally linked to leptin-induced decreases in food intake and body weight and increases in SNA. SFO-targeted microinjections of an adenovirus encoding Cre-recombinase in ObR(flox/flox) mice resulted in selective ablation of ObR in the SFO. Interestingly, deletion of ObR in the SFO did not influence the decreases in either food intake or body weight in response to daily systemic or cerebroventricular administration of leptin. In line with these findings, reduction in SFO ObR did not attenuate leptin-mediated increases in thermogenic brown adipose tissue SNA. In contrast, increases in renal SNA induced by systemic or cerebroventricular administration of leptin were abolished in mice with SFO-targeted deletion of ObR. These results demonstrate that ObR in the SFO play an important role in leptin-induced renal sympathoexcitation, but not in the body weight, food intake, or brown adipose tissue SNA thermogenic effects of leptin. These findings highlight the concept of a distributed brain network of leptin action and illustrate that brain regions, including the SFO, can mediate distinct cardiovascular and metabolic responses to leptin.

Angiotensin type 1a receptors in the subfornical organ are required for deoxycorticosterone acetate-salt hypertension.

Although elevated renin-angiotensin system activity and angiotensinergic signaling within the brain are required for hypertension, polydipsia, and increased metabolic rate induced by deoxycorticosterone acetate (DOCA)-salt, the contribution of specific receptor subtypes and brain nuclei mediating these responses remains poorly defined. We hypothesized that angiotensin type 1a receptors (AT(1a)R) within the subfornical organ (SFO) mediate these responses. Transgenic mice carrying a conditional allele of the endogenous AT(1a)R (AT(1a)R(flox)) were administered an adenovirus encoding Cre-recombinase and enhanced green fluorescent protein (eGFP) or adenovirus encoding eGFP alone into the lateral cerebral ventricle. Adenovirus encoding Cre-recombinase reduced AT(1a)R mRNA and induced recombination in AT(1a)R(flox) genomic DNA specifically in the SFO, without significant effect in the paraventricular or arcuate nuclei, and also induced SFO-specific recombination in ROSA(TdTomato) reporter mice. The effect of SFO-targeted ablation of endogenous AT(1a)R was evaluated in AT(1a)R(flox) mice at 3 time points: (1) baseline, (2) 1 week after virus injection but before DOCA-salt, and (3) after 3 weeks of DOCA-salt. DOCA-salt-treated mice with deletion of AT(1a)R in SFO exhibited a blunted increase in arterial pressure. Increased sympathetic cardiac modulation and urine copeptin, a marker of vasopressin release, were both significantly reduced in DOCA-salt mice when AT(1a)R was deleted in the SFO. Additionally, deletion of AT(1a)R in the SFO significantly attenuated the polydipsia, polyuria, and sodium intake in response to DOCA-salt. Together, these data highlight the contribution of AT(1a)R in the SFO to arterial pressure regulation potentially through changes on sympathetic cardiac modulation, vasopressin release, and hydromineral balance in the DOCA-salt model of hypertension.

ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension.

Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angiotensin II (Ang II). We tested the hypothesis that ER stress in the brain is causally linked to Ang II-dependent HTN. Chronic systemic infusion of low-dose Ang II in C57BL/6 mice induced slowly developing HTN, which was abolished by co-infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) into the lateral cerebroventricle. Investigations of the brain regions involved revealed robust increases in ER stress biomarkers and profound ER morphological abnormalities in the circumventricular subfornical organ (SFO), a region outside the blood-brain barrier and replete with Ang II receptors. Ang II-induced HTN could be prevented in this model by selective genetic supplementation of the ER chaperone 78-kDa glucose-regulated protein (GRP78) in the SFO. These data demonstrate that Ang II-dependent HTN is mediated by ER stress in the brain, particularly the SFO. To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease.

Cardiovascular and sympathetic effects of disrupting tyrosine 985 of the leptin receptor.

Leptin acts in the brain to regulate food intake and energy expenditure. Leptin also increases renal sympathetic nerve activity and arterial pressure. The divergent signaling capacities of the leptin receptor (ObRb) mediate the stimulation of various intracellular pathways that are important for leptin control of physiological processes. We evaluated the cardiovascular and sympathetic consequences of disrupting the signal emanating from tyrosine985 of ObRb. For this, we used Lepr(L985) (l/l) mice, which carry a loss of function mutation replacing tyrosine985 of ObRb with leucine. Body weight of l/l mice was not significantly different from wild-type controls. In contrast, radiotelemetry measurements revealed that the l/l mice had higher arterial pressure and heart rate as compared with controls. Ganglionic blockade caused a greater arterial pressure fall in the l/l mice relative to controls. In addition, leptin treatment induced a larger increase in arterial pressure and heart rate in the l/l versus wild-type mice. Finally, we compared the response of renal and brown adipose tissue sympathetic nerve activity to intracerebroventricular injection of leptin (2 µg) between l/l and control mice. Leptin-induced increase in renal sympathetic nerve activity was greater in l/l mice relative to controls. In contrast, the brown adipose tissue sympathetic nerve activity response to leptin was attenuated in the l/l mice relative to controls. These data indicate that selective loss of leptin receptor signaling emanating from tyrosine985 enhances the cardiovascular and renal sympathetic effects of leptin. These findings provide important insight into the molecular mechanisms underlying leptin's effects on the sympathetic cardiovascular function and arterial pressure.