Leptin crosses the blood–brain barrier, apparently via a receptor-mediated process, and activates its receptors in several regions of the CNS including the hypothalamus and brainstem. The most studied CNS action of leptin is its ability to reduce appetite and to increase energy expenditure. Leptin deficiency or leptin receptor (LR) mutations that prevent normal activation of its intracellular signaling events lead to early-onset, morbid obesity [17-19].
Leptin may Link Obesity with Increased Sympathetic Activity and Hypertension
Despite marked obesity and many other characteristics of the metabolic syndrome including hyperinsulinemia, dyslipidemia, hyperglycemia, visceral adiposity and insulin resistance, rodents and humans with leptin gene or LR mutations are not hypertensive and do not exhibit increased SNS activity [19-22]. In fact, humans with leptin gene mutation show postural hypotension and attenuated renin–angiotensin–aldosterone system responses to upright posture . Mice with leptin deficiency (ob/ob mice) tend to have lower BP than lean control mice despite severe obesity and metabolic abnormalities that would normally tend to raise BP [20, 22]. These findings suggest that a functional leptin system may be necessary for obesity to increase SNS activity and raise BP. Further evidence supporting a role for leptin in contributing to SNS activation and hypertension in obesity also comes from the studies, showing that leptin administration, either peripherally or directly into the brain, raises renal SNS activity and BP [2, 23-28]. Moreover, chronic leptin infusion in lean rodents causes gradual and sustained increases in BP that can be completely prevented by chronic α and β adrenergic receptor blockade . Transgenic mice that overexpress leptin also exhibit increased BP which can be reversed by adrenergic blockade . Taken together, these observations indicate that 1) increased circulating levels of leptin, comparable to those found in obesity, can raise BP and SNS activity and 2) a functional leptin system is required for obesity to increase SNS activity and BP.
Selective Leptin Resistance in Obesity
The fact that most obese humans have high circulating leptin levels and continue to ingest excess calories is consistent with the concept that obesity causes resistance to the anorexic effects of leptin. Experimental studies have also shown that leptin is much less effective in suppressing appetite in obese than in lean animals [30, 31]. To the extent that obesity induces global resistance to leptin, including the SNS response to leptin, one would expect the chronic hypertensive actions of leptin to also be attenuated in obese subjects. However, it appears that obesity may induce “selective” leptin resistance, whereby the renal SNS responses to leptin are maintained, whereas the appetite suppressant effects of leptin are attenuated . Although there is experimental support for this concept [23-26, 30], there have been few studies that have tested whether the chronic effects of hyperleptinemia on BP and SNS activity are attenuated in obese compared to lean subjects. The CNS pathways and cell signaling mechanisms that underlie selective leptin resistance in obesity are only beginning to be elucidated and represent an important area for investigation.
Intracellular Signaling Events and Selective Activation of LRs in Specific Areas of the CNS may Contribute to Selective Leptin Resistance in Obesity
The LR is a cytokine receptor that activates Janus tyrosine kinases (JAKs), especially JAK2 . Activation of LR increases activity of intracellular JAK2. In the CNS, LR-induced activation of JAK2 triggers three major intracellular pathways: 1) phosphorylation of tyrosine (Tyr) residue 1138 leads to recruitment of latent signal transducers and activators of transcription 3 (STAT3) to the LR–JAK2 complex, resulting in phosphorylation and nuclear translocation of STAT3 to regulate transcription. This pathway is thought to play a major role in the regulation of body weight homeostasis by leptin; 2) insulin receptor substrate (IRS2) phosphorylation activates phosphatidylinositol 3-kinase (PI3K) which appears to be involved in regulating rapid nongenomic events affecting neuronal activity and neuropeptide release and 3) Tyr985 phosphorylation recruits the tyrosine phosphatase (SHP2) to activate the ERK (MAPK) pathway (Fig. 1) which may contribute to the effects of leptin on thermogenesis and peripheral glucose utilization.
Figure 1. LR signaling pathways. Shp2, tyrosine phosphatase; IRS, insulin receptor substrate; STAT3, signal transducers and activators of transcription 3; SOCS, suppressor of cytokine signaling; PTP1B, protein tyrosine phosphatase; NPY, neuropeptide Y; AgRP, agouti-related protein. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Deletion of each of these signaling pathways in the CNS results in varying degrees of obesity although only neuron-specific deletion of the STAT3 pathway appears to mimic the obese phenotype found in ob/ob mice . Deletion of STAT3 in the entire CNS also causes hyperphagia and attenuated leptin-induced anorexia. We recently showed that deletion of STAT3 specifically in POMC neurons results only in mild obesity associated with normal responses to leptin on appetite and thermogenesis . However, deletion of STAT3 in POMC neurons markedly attenuated leptin's ability to raise BP . These observations suggest that leptin-induced STAT3 activation in POMC neurons is important for BP regulation, whereas STAT3 activation in other groups of neurons is more important in mediating the effects of leptin on appetite and energy expenditure.
Previous acute studies also suggest that activation of the IRS2–PI3K pathway may contribute to leptin's ability to increase SNS activity and BP. For instance, pharmacological blockade of PI3K abolished the acute effects of leptin to increase renal SNS activity . To our knowledge, however, no long-term studies have been conducted to test whether chronic blockade of the IRS2–PI3K pathway abolishes or attenuates the chronic effects of sustained hyperleptinemia to increase SNS activity and BP. Deletion of IRS2 in the entire CNS causes only moderate obesity and slight hyperphagia associated with normal anorexic and weight loss responses to leptin [36-38]. These observations indicate that although IRS2–PI3K signaling modestly contributes to body weight homeostasis but may mediate, at least in part, the action of leptin on SNS activity. Further studies are needed, however, to assess the role of this pathway in mediating the chronic effects of leptin on renal SNS activity and BP in obesity.
The Shp2–MAPK pathway plays an important role in controlling energy balance and metabolism as evident by the finding that pan-neuronal deletion of Shp2 causes obesity associated with hyperphagia and diabetes . Deletion of Shp2 specifically in forebrain neurons, however, has been reported to cause early-onset obesity and metabolic syndrome mainly by reducing energy expenditure rather than promoting increased food intake . Although these observations support an important role for Shp2 signaling in regulation of appetite, energy expenditure and glucose homeostasis, no previous studies, to our knowledge, have directly examined the role of Shp2 in mediating the actions of leptin on appetite, metabolism and cardiovascular regulation including regulation of SNS activity and BP.
Collectively, these observations are consistent with the possibility that differential activation of these three intracellular signaling pathways by the LR may mediate divergent control of appetite, energy balance, glucose homeostasis and cardiovascular function and may help explain the development of selective leptin resistance in obesity. LR activation in different regions of the CNS may also contribute to the development of selective leptin resistance in obesity. High levels of LR mRNA and protein are expressed in the forebrain, especially in the ventromedial hypothalamus, arcuate nucleus (ARC) and dorsomedial hypothalamus . However, LR mRNA and immunoreactivity are also highly expressed in extra-hypothalamic brain regions, including the vasomotor centers of the brainstem . Thus, depending on its site of action leptin may control appetite independently of its effect to increase SNS activity and BP.
Vong et al.  showed that LR deletion in gabaergic neurons mimics most of the obese phenotypes observed in ob/ob mice. Although the authors suggest that leptin's action on presynaptic gabaergic neurons decreases inhibitory tone to postsynaptic POMC neurons, the mechanism responsible for obesity in these mice remains unclear. In addition, gabaergic neurons are widely distributed in the CNS and further studies are still needed to examine which neuronal types and brain sites are most important in mediating the effects of leptin on appetite and body weight homeostasis as well as on SNS activity. Deletion of LRs in the ARC of the hypothalamus markedly reduced the acute effects of leptin to increase renal SNS activity and attenuated the rise in BP induced by high-fat feeding . We have shown that activation of LRs specifically in POMC neurons, which are present in the ARC and brainstem, is critical for leptin's ability to increase BP and improve glucose homeostasis but not for its effect to reduce appetite . These findings suggest that activation of LR in POMC neurons is necessary for the chronic effects of leptin on BP regulation and certain metabolic functions, whereas LR activation in other neurons appears to play a more important role in mediating the effects of leptin on appetite and energy balance  (Fig. 2).
Figure 2. Leptin–brain melanocortin system interaction. Schematic representation of the metabolic and cardiovascular effects of the leptin–melanocortin system pathway. CNS, central nervous system; Na, sodium; MC4R, melanocortin-4 receptor; POMC, pro-opiomelanocortin; SNS, sympathetic nervous system. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Another potential mechanism contributing to selective leptin resistance in obesity is differential control of LR signaling by negative regulators such as protein tyrosine phosphatase-1B (PTP1B) and suppressor of cytokine signaling (Socs3) (Fig. 1), both of which may be altered in obesity. PTP1B regulates the JAK/STAT3 signaling pathway by dephosphorylation of JAK2 , whereas Socs3 negatively regulates LR signaling by inhibiting JAK activity . Deletion of PTP1B enhances leptin sensitivity and confers resistance to high-fat-diet-induced obesity and type II diabetes . Mice with whole-body PTP1B deficiency also exhibit higher baseline BP and amplified BP response to leptin compared to wild-type controls . In addition, specific deletion of PTP1B in POMC neurons does not alter food intake but increases energy expenditure, suggesting that alterations in PTP1B levels in certain areas of the brain or in specific neuronal types (e.g., POMC neurons) may modulate SNS activity and BP with minimal effect on the anorexic action of leptin.
Socs3 expression is regulated by the STAT3 pathway and, like PTP1B, is a negative regulator of LR signaling that may contribute to leptin resistance. For example, Socs3 deficiency increases leptin sensitivity and attenuates development of obesity caused by a high-fat diet [47, 48]. The importance of Socs3 signaling in regulating SNS activity, however, remains unclear. Together, PTP1B and Socs3 could play an important role in modulating the appetite, metabolic and cardiovascular actions of leptin and contribute to the development of selective leptin resistance in obesity. However, additional studies are needed to explore how obesity alters PTP1B and Socs3 expression and whether these negative regulators of LR signaling may be potential targets for novel therapies to treat obesity and its metabolic and cardiovascular abnormalities.