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Endocrinology Vol. 145, No. 6 2613-2620
Copyright © 2004 by The Endocrine Society

Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin

Abhiram Sahu

Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Abhiram Sahu, Ph.D, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, S-829 Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15262. E-mail: asahu{at}pitt.edu


   Abstract
Top
 Abstract
Introduction
 Hypothalamus as an Integrator...
 Hypothalamic Neuropeptidergic...
 Leptin Action in the...
 Conclusions
 References
 
The hypothalamus is a major site for integration of central and peripheral signals that regulate energy homeostasis. Within the hypothalamus, neurons residing in the ARC (arcuate nucleus)-PVN (paraventricular)-PF/LH (perifornical/lateral hypothalamus) axis communicate among each other and are subjected to the influence of several peripheral factors, including leptin and insulin. Proper signaling in the hypothalamus by leptin, a long-sought peripheral factor that relays the status of fat stores, is critical to normal regulation of food intake and body weight. Leptin action in the hypothalamus is mediated by a large number of orexigenic and anorectic peptide-producing neurons of the ARC-PVN-PF/LH axis. Not only the classical JAK2 (Janus kinase 2)-STAT3 (signal transducer and activator of transcription 3) pathway, but also the phosphatidylinositol-3 kinase-phosphodiesterase 3B-cAMP pathway mediates hypothalamic leptin receptor signaling. It appears that hypothalamic leptin resistance, possibly due to defective nutritional regulation of leptin receptor expression and/or reduced STAT3 signaling in the hypothalamus, contributes to the development of obesity associated with high-fat feeding and aging. Interestingly, hypothalamic neurons may develop leptin resistance despite an intact JAK2-STAT3 signaling path. The role of suppressor of cytokine signaling 3 and other negative regulators of leptin signaling in central leptin resistance needs to be established, an important area of future investigation. Further understanding of the neural circuitry and leptin signaling in the hypothalamus is critical not only for the advancement of our knowledge on the hypothalamic role in energy balance but also for future development of drugs for the attenuation or treatment of obesity and related disorders in humans.


   Introduction
Top
 Abstract
 Introduction
Hypothalamus as an Integrator...
 Hypothalamic Neuropeptidergic...
 Leptin Action in the...
 Conclusions
 References
 
OBESITY IS A MAJOR health hazard in humans, particularly in Western societies. Genetic (monogenic, susceptible gene) and environmental (diet, exercise, social factors, chemicals, etc.), factors are involved in the development of obesity (1). However, the bottom line is that an increase in energy intake that is greater than energy expenditure leads to positive energy balance; excess calories are stored in the form of fat. Continuous increases in fat mass eventually lead to obesity. Thus, to understand the mechanisms of obesity, it is imperative to understand the mechanisms underlying food intake and body weight regulation.

The hypothalamus is a primary site of integration of several factors of central and peripheral origin for the regulation of energy homeostasis. This review focuses on the actions of leptin on hypothalamic neural circuitry controlling food intake and body weight. The neural circuitry in the hypothalamus that controls energy homeostasis will be described briefly. Then, recent advances in understanding intracellular signal transduction mechanisms in mediating leptin action will be discussed, as well as the possible mechanisms underlying leptin resistance in the hypothalamus.


   Hypothalamus as an Integrator of Energy Balance
Top
 Abstract
 Introduction
 Hypothalamus as an Integrator...
Hypothalamic Neuropeptidergic...
 Leptin Action in the...
 Conclusions
 References
 
The role of hypothalamus in body weight control was established by lesion studies of Hetherington and Ranson (2) and by Anand and Brobeck (3), who showed that lesions in the ventromedial hypothalamus (VMH) caused hyperphagia and obesity, lesions in the lateral hypothalamus (LH) caused aphagia and even death by starvation. In subsequent studies using parabiotic rats, in which one of the parabiotic partners had a VMH lesion and developed obesity, Hervey (4) showed that the intact partner became anorexic and lean. Rats with VMH lesions are refractory to leptin action in the hypothalamus (5).

Overall, several hypothalamic sites including the ARC, VMH, dorsomedial (DMN), and PVN nuclei and the LH are implicated in food intake and body weight regulation. An array of orexigenic and anorectic peptides that constitute a major part of the neural circuitry regulating feeding behavior and body weight are primarily produced by the neurons localized in these hypothalamic areas. It is now established that the neural circuitry as well as the peripheral factors that impinge on it are comprised of both orexigenic and anorectic signals. Peptidergic signals involved in energy homeostasis are presented in Table 1Go. In addition, other signals such as catecholamines, serotonin, sex steroids, and glucocorticoids also play significant roles in energy homeostasis. Nevertheless, the hypothalamus is a primary site of integration of all of these signals.


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  		TABLE 1. Peptidergic signals that stimulate or inhibit food intake

 

   Hypothalamic Neuropeptidergic Circuitry in Food Intake and Body Weight Regulation
Top
 Abstract
 Introduction
 Hypothalamus as an Integrator...
 Hypothalamic Neuropeptidergic...
Leptin Action in the...
 Conclusions
 References
 
Hypothalamic neuropeptidergic circuitry controlling energy homeostasis is comprised of a large number of orexigenic and anorectic peptides (Table 1Go), which have been described elsewhere in detail (6, 7, 8, 9). Among the neuropeptidergic systems, two neuronal types in the ARC, the neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, have been studied extensively because of their critical opposite roles in food intake. NPY is the most potent endogenous orexigenic signal. NPY neuronal activity is enhanced before the onset of natural feeding, in hyperphagia seen in experimental diabetes and with obesity (see Refs.6, 7, 8, 9, 10, 11). NPY neurons in the ARC coexpress agouti-related protein (AgRP), also an orexigenic peptide (7, 8), and an endogenous antagonist of {alpha}-MSH at central melanocortin receptors (8). Repeated or continuous central infusion of NPY or AgRP results in obesity (12, 13). In addition, knocking out NPY in the ob/ob mice reduces food intake and obesity (14), suggesting a contribution of NPY in the hyperphagia and increased body weight in ob/ob mice. By contrast, NPY knockout mice are phenotypically normal (15), suggesting redundant signaling mechanisms in the hypothalamus.

In contrast to the NPY/AgRP neurons, POMC neurons are involved in reducing food intake and body weight by releasing {alpha}-MSH, which binds with high affinity to melanocortin receptors 3 and 4 (MC3/MC4) (16). Both MC3 and MC4 receptors are localized in the hypothalamus, MC4 receptor –/– mice become obese, and MC4 receptor mutation causes obesity in mice and humans (16, 17). In the ARC, POMC neurons also coexpress cocaine- and amphetamine-related peptide (CART), also a potent inhibitor of food intake (18, 19). Although, recent evidence showing increased food intake and body weight after daily injection of CART or overexpression of CART in the ARC suggests that anorectic effect of CART seen after intracerebroventricular injection may be indirect working at the hindbrain site (20), the role of CART in energy homeostasis requires further investigation. However, altering food intake changes POMC/CART mRNA in the hypothalamus (8, 16, 18). Finally, mutation in the POMC gene results in obesity (17), suggesting a critical role of melanocortin signaling in the hypothalamic regulation of energy homeostasis. It appears that CRH, a potent anorectic peptide, acts as a downstream mediator of melanocortin signaling in that CRH neurons express MC4R mRNA, melanocortin agonist MTII induces CRH gene expression in the PVN, and CRH receptor antagonist partially blocks anorectic effect of MTII (21).

Among other orexigenic peptide-producing neurons, melanin-concentrating hormone (MCH) neurons localized in the LH appear to play a significant role in energy homeostasis. MCH stimulates food intake, MCH gene expression shows reciprocal changes in response to fasting and refeeding, MCH overexpression in the hypothalamus results in obesity, MCH ablation in ob/ob mice decreases body weight by increasing energy expenditure, MCH knockout mice are hypophagic and lean with increased metabolism and finally MCH receptor ablation leads to lean phenotype (22, 23). MCH is also a functional melanocortin antagonist (22). Furthermore POMC/CART and NPY/AgRP neurons innervate MCH neurons (19), and functional interactions among NPY, MCH, and anorectic peptides (24) exist, supporting a significant role of MCH neurons in energy homeostasis.

Recently, the role of several other hypothalamic neuronal systems such as 26RFa (25); brain-derived neurotrophic factor (BDNF;26); prolactin-releasing peptide (PrRP;27); neuropeptides B and W, ligands for G protein-coupled receptor-7 (GPR7;28, 29, 30); ghrelin (31, 32); and galanin-like peptide (GALP;33) on food intake and body weight have been found and will be described here. 26RFa, a hypothalamic neuropeptide of the RFamide peptide family, expressed exclusively in the VMN and LH, is a potent orexigenic peptide in mice, and warrants further studies (25).

BDNF, a member of the family of neurotropins, is expressed highly in the VMH and moderately in the PVN and LH (34). Several lines of evidence suggest an important role of BDNF in energy homeostasis. Chronic central BDNF infusion dose dependently suppresses appetite and weight loss in rats (35); central or peripheral administration of BDNF decreases food intake and increases energy expenditure in db/db mice (36); mice with conditional deletion of BDNF (37) or BDNF heterozygous mice develop hyperphagia and adult onset obesity (34, 38); food deprivation reduces BDNF expression in the VMH (26); the BDNF receptor TrkB is localized in the hypothalamus (34), and TrkB mutant mice develop hyperphagia and severe obesity (26). It appears that melanocortins regulate BDNF expression in the VMH because BDNF expression in this area is reduced in the Ay (agouti overexpressing) mutant mice, and the MC4 agonist, MTII, significantly increases the level of BDNF mRNA in the VMH of food-deprived mice (26). Also, central BDNF infusion suppresses the hyperphagia and excessive weight gain observed on high-fat (HF) diets in mice with deficient MC4 signaling (26). These results suggest that BDNF is an important effector, through which MC4R signaling controls energy balance (26). Altogether, it is conceivable that BDNF could be a missing piece in the puzzle behind the mechanisms of the development of obesity seen after VMH lesion (2).

PrRP, a ligand for the human orphan G protein-coupled receptor hGR3/GPR10, was originally reported to cause prolactin secretion from anterior pituitary cells (27). Recent studies suggest a role of PrRP in the regulation of food intake (39, 40). Specifically, PrRP and its receptor are localized in the hypothalamus (41, 42); central infusions of PrRP decrease feeding and body weight gain (39, 40), cause hyperthermia, and increase uncoupling protein-1 mRNA expression and oxygen consumption (43, 44). PrRP mRNA is reduced in situations of negative energy balance (39, 40) and in chronic genetic obesity (45). CRH and its receptors appear to mediate anorectic and body weight reducing effect of PrRP (40, 44, 46). PrRP also interacts with leptin to reduce food intake and body weight, and PrRP neurons express leptin receptors (45). Thus, an important role of PrRP in energy homeostasis is emerging.

Recent evidence strongly suggests potential role of GPR7 and its ligands in energy homeostasis. Targeted disruption of GPR7, the endogenous receptor for neuropeptides B (NPB) and W (NPW), leads to metabolic defects and adult-onset obesity in a sexually dimorphic manner, i.e. these defects occur only in males, in association with hyperphagia, decreased energy expenditure and locomotor activity (30); GPR7 is highly expressed in the ARC and VMH (47, 48); central injection of NPB or NPW alters food intake (28). These results suggest that GPR7 may also be important in energy homeostasis.

GALP, a recently identified neuropeptide, is highly expressed in the ARC (see Ref.33). In rats, a biphasic action of GALP on feeding is evident; within 2 h of intracerebroventricular administration, GALP stimulates feeding, at 24 h both feeding and body weight are significantly reduced (49). In mice, however, GALP elicits a dose-dependent decrease in both feeding and body weight (49). Other evidence (see Leptin action on hypothalamic peptides governing feeding and energy homeostasis) such as that fasting reduces GALP mRNA levels (49) and leptin induces GALP mRNA levels in the hypothalamus (50) suggest that GALP is one of the anorectic signals in the neural circuitry regulating energy balance.

Ghrelin is primarily produced in the stomach and is the first systemically active orexigenic hormone; both central and peripheral administration of ghrelin stimulates feeding and reduces energy expenditure leading to increased body weight (19, 31, 51). Ghrelin is also produced in the hypothalamus, and these neurons send axons onto NPY/AGRP, POMC, and CRH neurons (32). Ghrelin receptors are localized in the hypothalamus, particularly in NPY/AgRP neurons (19). Although ghrelin’s orexigenic effect is primarily mediated by engaging NPY/AgRP neurons (19), recent evidence suggests that it also engages orexin neurons (52, 53). Furthermore, ghrelin injection either into the PVN or LH stimulates feeding and activates c-Fos in the PVN, ARC, DMN, and other brain areas (53, 54), suggesting the PVN and LH as parts of the central circuitry involved in ghrelin’s orexigenic effect. Interestingly, ghrelin knockout mice do not show any impairment in growth or appetite (55).


   Leptin Action in the Hypothalamus in Control of Energy Homeostasis
Top
 Abstract
 Introduction
 Hypothalamus as an Integrator...
 Hypothalamic Neuropeptidergic...
 Leptin Action in the...
Conclusions
 References
 
Leptin, a long-sought body weight regulating factor of peripheral origin
Although the idea of a blood-borne factor originating from the fat mass playing a critical role in body weight regulation through acting at the hypothalamus has been conceptualized from the days of Kennedy through Douglas Colemen’s study (56, 57), this factor was finally identified as leptin by Friedman’s group (58). The discovery of the leptin receptor by Tartaglia’s group (59) has intensified leptin research, and the physiological role of leptin has been appreciated in a variety of physiological functions including energy homeostasis, reproduction, bone formation, and cardiovascular systems. Expectedly, leptin signals nutritional status to key regulatory centers in the hypothalamus, and it has emerged as an important signal regulating energy homeostasis (7, 8, 19, 60, 61, 62). Leptin administration either centrally or peripherally decreases food intake and body weight. Deficiency in leptin action due to mutation in the leptin gene or the leptin receptor is associated with massive obesity in humans and rodents (17, 61). In addition, leptin corrects obesity-related metabolic and endocrine defects in ob/ob mice and blunts starvation-induced abnormalities in the gonadal, adrenal, and thyroid axes in lean mice (61, 63).

Leptin action on hypothalamic peptides governing feeding and energy homeostasis
Initial findings that central injections of leptin were more potent than peripheral injections clearly suggested the hypothalamus as the major site of leptin action in energy homeostasis (60). Subsequent studies showing high expression of long-signaling form of the leptin receptor (Ob-Rb) in the hypothalamus, and identification of several orexigenic and anorectic peptide-producing neurons as targets of leptin signaling have strongly established hypothalamus as a primary site of leptin action in body weight regulation. Leptin target neurons are mainly localized in the ARC, LH, and PVN, areas that are known to be major sites of production and integration of neural signals involved in energy homeostasis. Among the leptin-sensitive neurons, NPY/AgRP and POMC/CART neurons of the ARC have been studied extensively. NPY/AgRP is orexigenic and POMC/CART is anorectic, and leptin reduces NPY/AgRP neuronal activity and stimulates POMC/CART neuronal activity as expected (8, 19, 62). Leptin action on POMC neurons may also involve reduction of {gamma}-aminobutyric acid and AgRP release from the NPY/AgRP neurons (64). A significant role of POMC/CART neurons in mediating leptin action is further evident from the fact that POMC neurons are glucose responsive and express K-ATP channels, and leptin activates K-ATP channels in POMC neurons (65).

Among other leptin-target neurons, MCH, galanin (GAL), GALP, orexin, neurotensin (NT), and CRH producing neurons are notable. Leptin decreases MCH, GAL, and orexin gene expression (66, 67) and increases GALP, NT, and CRH gene expression in the hypothalamus (67, 68, 69). Leptin increases GALP-expressing cells in ob/ob mice, and GALP neurons express leptin receptors (33), suggesting a potential role of GALP in mediating leptin action. The evidence that leptin’s satiety action is blocked by prior administration of NT antibody or specific NT receptor antagonist (70); and that NT acts synergistically with leptin in reducing food intake (71), indicates a significant role of NT in leptin signaling in the hypothalamus. Anorectic PrRP neurons express leptin receptors and interact with leptin to reduce food intake, suggesting PrRP neurons as potential targets of leptin signaling (45). Evidence also suggests that leptin inhibits the actions of MCH, galanin, and NPY on feeding (72). Ghrelin and leptin functionally interact in that ghrelin blocks the effects of leptin on feeding and prior leptin administration attenuates the effects of ghrelin on feeding (73); leptin attenuates ghrelin’s action on NPY neurons (74). Thus, regulation of ghrelin’s effect on hypothalamic neurons, particularly NPY/AgRP neurons, may be one of the important mechanisms of leptin signaling in the hypothalamus.

Overall, leptin action in the hypothalamus is mediated by a large number of orexigenic and anorectic peptides in the ARC-PVN-PF/LH axis. It appears that leptin not only modifies gene expression of these neuropeptides, it also modifies the action of these peptides after they are secreted. Morphological connections and functional interactions seen between orexigenic and anorectic neurons (62, 75) suggest that leptin could alter (enhance or decrease) interactions between orexigenic and anorectic signals to fulfill its role in energy homeostasis. Recent studies by Friedman’s group show that in ob/ob mice, whereas excitatory and inhibitory synapses dominate NPY and POMC neurons, respectively; NPY perikarya become dominated by inhibitory synapses and the POMC perikarya are targeted predominantly by stimulatory inputs after 6 h of leptin infusion (76). The authors proposed that the anorectic effect of leptin is mediated, at least in part, by rapid changes in synaptic plasticity resulting in alteration in NPY and POMC tone in the hypothalamus, an interesting area of future research. Perhaps, changes in synaptic plasticity could also be involved in transducing action of other metabolic signals.

Leptin signal transduction mechanism in the hypothalamus, the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway
Leptin receptor is a member of the class 1 cytokine receptor family (77). Among six splice variants of the leptin receptor, Ob-Rb is clearly the mediator of leptin signaling in various tissues including the hypothalamus. Along this line, Ob-Rb is highly expressed in the hypothalamus and most if not all of the leptin-sensitive neurons express leptin receptor (78). As expected, the JAK-STAT pathway was promptly established to be the major pathway of leptin signaling in the hypothalamus (79). Among several STAT proteins, leptin only increases STAT3 phosphorylation and STAT3 DNA-binding activity in the hypothalamus (78, 79), particularly in the ARC, LH, VMN, and DMN (80). Several leptin sensitive neurons including NPY, POMC, galanin, and orexin neurons express STAT3 (78, 81), and it is likely that other Ob-R expressing neurons do also express STAT3, unless leptin signaling is mediated by a mechanism other than STAT3 activation in these neurons. Recent study by Bates et al. (82) suggests that leptin’s effect on NPY neurons may not be dependent on STAT3 activation.

Leptin signaling through JAK2-STAT3 pathway is thought to be under the negative feedback control of suppressor of cytokine signaling 3 (SOCS3) protein. Although over expression of SOCS3 reduces JAK-STAT signaling in mammalian cell lines (83), and leptin induces SOCS3 in the hypothalamus (84) and activates SOCS3 in NPY and POMC neurons (19, 85), the role of SOCS3 in leptin signaling in the hypothalamus remains unclear. Protein tyrosine phosphatase 1B (PTP1B), another negative regulator of leptin receptor signaling (86, 87), is localized in the hypothalamic areas where Ob-Rb is localized (87), and PTP1B knockout mice are resistant to DIO (diet-induced obesity) and more sensitive to leptin (88, 89), suggesting a significant role of PTP1B in leptin signaling in the hypothalamus. It is likely that interaction between SOCS3 and PTPIB could be critical during normal leptin signaling and that occurs during the development of leptin resistance.

Hypothalamic leptin signaling through phosphatidylinositol-3 kinase (PI3K)-phosphodiesterase 3B (PDE3B)-cAMP pathway
Although in several nonneuronal tissues, an insulin-like signaling pathway involving PI3K-dependent activation of PDE3B and eventual reduction of cAMP mediates leptin action (90, 91), the role of this pathway in transducing leptin action in the hypothalamus was not established until recently (92, 93). The idea that regulation of hypothalamic cAMP levels could play an important role in energy homeostasis, and therefore in leptin signaling in the hypothalamus came from the evidences such as intrahypothalamic cAMP injection increases food intake (94), central dibutyryl cAMP injection increases hypothalamic levels of NPY (95), and leptin modifies cAMP response element-mediated gene expression including that of NPY neurons in the hypothalamus (96). Notably, intracellular cAMP levels are regulated by adenylyl cyclase and cAMP PDEs (97). Cyclic nucleotide PDEs are a large super family of enzymes consisting currently of 20 different genes subgrouped into 11 different families (98, 99). PDE3B, one of the two members of type 3 PDE family of genes (98), is localized in several peripheral tissues and in the central nervous system including the hypothalamic ARC, VMN, DMN, PVN, LH, and perifornical hypothalamic areas (62, 100). The notion that PDE3B-cAMP pathway is involved in leptin signaling in the hypothalamus is evident from our demonstrations that leptin induces PDE3B activity and reduces cAMP levels in the hypothalamus, and that PDE3 inhibition by cilostamide, a specific PDE3 inhibitor, reverses the effect of leptin on food intake and body weight (78). Cilostamide also reverses leptin-induced STAT3 activation, suggesting a cross talk between the PDE3B-cAMP and JAK2-STAT3 pathways of leptin signaling in the hypothalamus (78). In addition, leptin activates PI3K activity in the hypothalamus (78, 93), PI3K inhibitors reverse anorectic action of leptin (93) and PI3K is localized in the arcuate nucleus (101). In addition, PI3K appears to be an upstream regulator of PDE3B in leptin signaling pathway in the hypothalamus (my unpublished observation), as seen in nonneuronal tissues (92). In total, it appears that a PI3K-PDE3B-cAMP pathway interacting with the JAK2-STAT3 pathway constitutes a critical component of leptin signaling in the hypothalamus (Fig. 1Go). This may be a common pathway for leptin and insulin signaling in the hypothalamus (62, 102, 103).



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  		FIG. 1. Schematic of leptin intracellular signaling in the hypothalamus. Leptin binding to its receptor (Ob-Rb) induces activation of JAK2, receptor dimerization, and JAK2-mediated phosphorylation of the intracellular part of the receptor, followed by phosphorylation and activation of STAT3. Activated STAT3 dimerizes, translocates to the nucleus, and trans-activates target genes, including SOCS3, NPY, and POMC. Our evidence suggests that leptin also activates PI3K and PDE3B and reduces cAMP levels in the hypothalamus, and that the PI3K-PDE3B-cAMP pathway interacting with the JAK2-STAT3 pathway constitutes a critical component of leptin signaling in the hypothalamus. We hypothesize that defects in either one or both of the signaling pathways may be responsible for the development of leptin resistance seen in obesity. Other potential signaling pathways including the involvement of Src homology 2-domain containing protein-tyrosine phosphatase-growth receptor bound 2 (SHP2-GRB2)-Ras-Raf-MAPK/ERK pathway and PTP1B in regulating leptin action in the hypothalamus are left out to simplify the figure. IRS, Insulin receptor substrate. [Adapted from Ref.62 .]

 
Hypothalamus, obesity, and leptin resistance
Normal function of the hypothalamic neural circuitry, which is tightly regulated by signals relaying peripheral energy status to the hypothalamus, is critical for the maintenance of stable body weight. In line with its physiological role in energy homeostasis, deficiency in leptin signaling due to absence of leptin (e.g. ob/ob) or leptin receptor (e.g. db/db) or lack of proper leptin functioning in the hypothalamus (e.g. DIO) results in obesity. Because hyperleptinimia in majority of obese people suggests a state of leptin resistance (leptin resistance may be defined as reduced sensitivity or complete insensitivity to leptin action), understanding the mechanism behind the development of leptin resistance has been the subject of intensive research.

Leptin signaling during the development of central leptin resistance in DIO and in aging-associated obesity
Although a defective leptin transport is thought to be one of the many factors behind the development of leptin resistance (see Ref.104), recent evidence strongly suggests that central leptin resistance also contributes to the development of obesity. For example, anorectic effect of central leptin is reduced in DIO rats (105, 106) and DIO mice (107); nutritional regulation of leptin receptor gene expression in the hypothalamus is defective in DIO rats (108) and leptin signaling through STAT3 is reduced in DIO mice (109). In addition, in obesity-prone rats, Ob-Rb gene expression and leptin-induced STAT3 activation in the hypothalamus are compromised before the development of obesity or exposure to HF diet (110). Although there is some evidence for the possible development of leptin resistance in NPY/AgRP neurons during DIO (111, 112), it is, however, important to demonstrate how and when the changes, if any, in leptin sensitivity to these and other leptin target neurons occur during the development of DIO. As in DIO, age-related obesity is associated with both central and peripheral leptin resistance (113). Thus, the effects of central or peripheral injection of leptin on feeding, uncoupling protein-1 mRNA levels in the brown adipose tissue, oxygen consumption and hypothalamic NPY mRNA levels and STAT3 activation are significantly reduced in aged compared with that in young F-344xBN rats (113). In old Wistar rats, anorectic and body weight-reducing effects of central leptin are attenuated (114), and leptin uptake and Ob-Rb mRNA levels in the hypothalamus are reduced (115).

Leptin resistance after chronic elevation of hypothalamic leptin tone
Recently, we have demonstrated that in rat, NPY, POMC, and NT neurons developed leptin resistance within 2 wk chronic central leptin infusion (116, 117) but without any defect in leptin signal transduction through the JAK2-STAT3 pathway (118). Interestingly, a defective PDE3B-cAMP pathway of leptin signaling in the hypothalamus was evident because enhanced PDE3B activity and reduction of cAMP levels in the hypothalamus seen on d 2 was not observed on d 16 of leptin infusion (119). These findings suggest that this rat model of central leptin infusion can be used to elucidate mechanism of central leptin resistance, and that leptin signaling through the P13K-PDE3B-cAMP pathway in the hypothalamus is critical and warrants further investigations of this pathway during the development of obesity. Notably, leptin-induced leptin resistance does also occur after central rAAV-leptin gene delivery in young lean and mildly obese aged rats (120, 121). Because leptin levels increase as early as d 1 of HF feeding (111), it is conceivable that chronic elevation of hypothalamic leptin tone may be involved in the development of leptin resistance seen in obesity.

Role of SOCS3 in central leptin resistance
SOCS3 is thought to be involved in leptin resistance (84, 85). However, JAK2-STAT3 signaling remains intact despite an increased SOCS3 gene expression and protein levels after chronic central leptin infusion (118). Similarly, rAAV-leptin-induced leptin resistance seen in mildly obese aged rats is associated with increase of both STAT3 activity and SOCS3 gene expression in the hypothalamus (120); and decreased STAT3 signaling in DIO mice is not associated with an increased SOCS3 mRNA expression (109). Thus, the role of SOCS3 in central leptin resistance is yet to be demonstrated, an important area for future investigations in understanding the hypothalamic mechanisms behind the development of obesity.


   Conclusions
Top
 Abstract
 Introduction
 Hypothalamus as an Integrator...
 Hypothalamic Neuropeptidergic...
 Leptin Action in the...
 Conclusions
References
 
Recent demonstration of a significant role of several newly identified signals such as GPR7 ligands, PrRP, GALP, and BDNF in transducing hypothalamic regulation of energy homeostasis has clearly advanced our understanding of the neural circuitry beyond simply NPY/AgRP and POMC/CART neuronal systems in the ARC. It appears that the neural circuitry not only includes both orexigenic and anorectic signals of hypothalamic origin, but accurate interactions between these signals and the metabolic signals originated in the periphery are critical for normal regulation of food intake and body weight. One of the peripheral signals whose signaling in the hypothalamus is essential for normal energy homeostasis is leptin. Leptin not only engages both orexigenic and anorectic peptide producing neurons in the ARC-PVN-LH axis, it also modifies postsynaptic action of orexigenic and anorectic signals. Besides the conventional JAK2-STAT3 pathway, the PI3K-PDE3B-cAMP pathway is one of the critical components of leptin signaling. The contribution of central leptin resistance in the development of DIO and aging-associated obesity is increasingly evident and therefore, further understanding of the mechanisms of leptin signaling is immensely important. Whereas defective nutritional regulation of leptin receptor expression, defective STAT3 signaling, and/or a defect downstream of leptin receptor signaling in specific cells such as NPY, POMC, and NT neurons appear to be involved in central leptin resistance, the role of SOCS3 in leptin resistance needs to be documented. The evidence of altered PDE3B-cAMP pathway of leptin signaling in association with leptin resistance in the hypothalamus after chronic central leptin infusion further attests the importance of this signaling pathway in leptin signaling, and suggests the possibility of a defective regulation of PI3K-PDE3B-cAMP pathway of leptin signaling in diet-induced obesity.


   Footnotes
 
This work was supported by National Institutes of Health Grants DK54484 and DK61499.

Abbreviations: AgRP, Agouti-related protein; ARC, arcuate nucleus; CART, cocaine- and amphetamine-related peptide; DIO, diet-induced obesity; DMN, dorsomedial nucleus; GALP, galanin-like peptide; HF, high-fat; JAK2, Janus kinase 2; LH, lateral hypothalamus; MC3/MC4, melanocortin receptors 3 and 4; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; NT, neurotensin; PDE3B, phosphodiesterase 3B; PF/LH, perifornical/lateral hypothalamus; PI3K, phosphatidylinositol-3 kinase; POMC, proopiomelanocortin; PTP1B, protein tyrosine phosphatase 1B; PVN, paraventricular nucleus; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; VMH, ventromedial hypothalamus.

Received January 13, 2004.

Accepted for publication March 16, 2004.


   References
Top
 Abstract
 Introduction
 Hypothalamus as an Integrator...
 Hypothalamic Neuropeptidergic...
 Leptin Action in the...
 Conclusions
 References
 

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