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• W2022366514 abstract "Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRbNts neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRbNts neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRbNts neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance. Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRbNts neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRbNts neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRbNts neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance. Neurotensin identifies a circumscribed subpopulation of LepRb neurons (LepRbNts) Loss of leptin signaling in LepRbNts neurons of Nts-LepRbKO mice results in obesity OX neurons and the mesolimbic DA system are dysregulated in Nts-LepRbKO mice Leptin controls OX, mesolimbic DA, and energy balance via LepRbNts neurons The increasing incidence of overweight and obesity predisposes millions of people to cardiovascular disease, type 2 diabetes, and reduced life span (Farag and Gaballa, 2011Farag Y.M. Gaballa M.R. Diabesity: an overview of a rising epidemic.Nephrol. Dial. Transplant. 2011; 26: 28-35Crossref PubMed Scopus (184) Google Scholar, Ogden et al., 2006Ogden C.L. Carroll M.D. Curtin L.R. McDowell M.A. Tabak C.J. Flegal K.M. Prevalence of overweight and obesity in the United States, 1999–2004.JAMA. 2006; 295: 1549-1555Crossref PubMed Scopus (7189) Google Scholar). Understanding the physiologic systems that control energy balance will be crucial to the rational development of effective therapies for obesity and related disorders. The adipose-derived hormone, leptin, acts via the long form of the leptin receptor (LepRb) to promote energy expenditure and to suppress feeding by modulating a host of neural systems and complex behaviors (Banks et al., 2000Banks A.S. Davis S.M. Bates S.H. Myers Jr., M.G. Activation of downstream signals by the long form of the leptin receptor.J. Biol. Chem. 2000; 275: 14563-14572Crossref PubMed Scopus (620) Google Scholar, Myers et al., 2009Myers Jr., M.G. Munzberg H. Leinninger G.M. Leshan R.L. The geometry of leptin action in the brain: more complicated than a simple ARC.Cell Metab. 2009; 9: 117-123Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, Pelleymounter et al., 1995Pelleymounter M.A. Cullen M.J. Baker M.B. Hecht R. Winters D. Boone T. Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice.Science. 1995; 269: 540-543Crossref PubMed Scopus (3777) Google Scholar, Vaisse et al., 1996Vaisse C. Halaas J.L. Horvath C.M. Darnell Jr., J.E. Stoffel M. Friedman J.M. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.Nat. Genet. 1996; 14: 95-97Crossref PubMed Scopus (915) Google Scholar). Commensurate with the diverse processes controlled by leptin, specialized groups of LepRb neurons lie in a variety of brain regions involved in energy balance; each LepRb population presumably modulates specific neural, physiologic, and behavioral functions. LepRb neurons in mediobasal hypothalamic centers (such as the ventromedial [VMH] and arcuate [ARC] nuclei) mediate aspects of leptin action on satiety and glucose homeostasis (Balthasar et al., 2004Balthasar N. Coppari R. McMinn J. Liu S.M. Lee C.E. Tang V. Kenny C.D. McGovern R.A. Chua Jr., S.C. Elmquist J.K. et al.Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.Neuron. 2004; 42: 983-991Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar, Coppari et al., 2005Coppari R. Ichinose M. Lee C.E. Pullen A.E. Kenny C.D. McGovern R.A. Tang V. Liu S.M. Ludwig T. Chua Jr., S.C. et al.The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity.Cell Metab. 2005; 1: 63-72Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, Dhillon et al., 2006Dhillon H. Zigman J.M. Ye C. Lee C.E. McGovern R.A. Tang V. Kenny C.D. Christiansen L.M. White R.D. Edelstein E.A. et al.Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.Neuron. 2006; 49: 191-203Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar, Hill et al., 2010Hill J.W. Elias C.F. Fukuda M. Williams K.W. Berglund E.D. Holland W.L. Cho Y.R. Chuang J.C. Xu Y. Choi M. et al.Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility.Cell Metab. 2010; 11: 286-297Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). The relatively modest body weight phenotype of animals null for LepRb in these mediobasal neural populations relative to the whole-body or hypothalamic deletion of LepRb suggests that other LepRb neurons contribute to the regulation of energy balance by leptin action (Balthasar et al., 2004Balthasar N. Coppari R. McMinn J. Liu S.M. Lee C.E. Tang V. Kenny C.D. McGovern R.A. Chua Jr., S.C. Elmquist J.K. et al.Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.Neuron. 2004; 42: 983-991Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar, Berthoud, 2007Berthoud H.R. Interactions between the “cognitive” and “metabolic” brain in the control of food intake.Physiol. Behav. 2007; 91: 486-498Crossref PubMed Scopus (190) Google Scholar, Dhillon et al., 2006Dhillon H. Zigman J.M. Ye C. Lee C.E. McGovern R.A. Tang V. Kenny C.D. Christiansen L.M. White R.D. Edelstein E.A. et al.Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.Neuron. 2006; 49: 191-203Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar, Elmquist et al., 2005Elmquist J.K. Coppari R. Balthasar N. Ichinose M. Lowell B.B. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis.J. Comp. Neurol. 2005; 493: 63-71Crossref PubMed Scopus (323) Google Scholar, Gao and Horvath, 2007Gao Q. Horvath T.L. Neurobiology of feeding and energy expenditure.Annu. Rev. Neurosci. 2007; 30: 367-398Crossref PubMed Scopus (261) Google Scholar, Morton et al., 2003Morton G.J. Niswender K.D. Rhodes C.J. Myers Jr., M.G. Blevins J.E. Baskin D.G. Schwartz M.W. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats.Endocrinology. 2003; 144: 2016-2024Crossref PubMed Scopus (140) Google Scholar, Ring and Zeltser, 2010Ring L.E. Zeltser L.M. Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels.J. Clin. Invest. 2010; 120: 2931-2941Crossref PubMed Scopus (85) Google Scholar, van de Wall et al., 2008van de Wall E. Leshan R. Xu A.W. Balthasar N. Coppari R. Liu S.M. Jo Y.H. MacKenzie R.G. Allison D.B. Dun N.J. et al.Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion.Endocrinology. 2008; 149: 1773-1785Crossref PubMed Scopus (249) Google Scholar). Indeed, several populations of LepRb neurons outside of the mediobasal hypothalamus have been suggested to contribute to energy balance (Fulton et al., 2006Fulton S. Pissios P. Manchon R.P. Stiles L. Frank L. Pothos E.N. Maratos-Flier E. Flier J.S. Leptin regulation of the mesoaccumbens dopamine pathway.Neuron. 2006; 51: 811-822Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar, Hayes et al., 2010Hayes M.R. Skibicka K.P. Leichner T.M. Guarnieri D.J. DiLeone R.J. Bence K.K. Grill H.J. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation.Cell Metab. 2010; 11: 77-83Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, Hommel et al., 2006Hommel J.D. Trinko R. Sears R.M. Georgescu D. Liu Z.W. Gao X.B. Thurmon J.J. Marinelli M. DiLeone R.J. Leptin receptor signaling in midbrain dopamine neurons regulates feeding.Neuron. 2006; 51: 801-810Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar, Leinninger et al., 2009Leinninger G.M. Jo Y.H. Leshan R.L. Louis G.W. Yang H. Barrera J.G. Wilson H. Opland D.M. Faouzi M.A. Gong Y. et al.Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.Cell Metab. 2009; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). Many aspects of physiologic leptin action remain poorly understood. For instance, leptin modulates orexin (OX; also known as hypocretin)-containing neurons (Diano et al., 2003Diano S. Horvath B. Urbanski H.F. Sotonyi P. Horvath T.L. Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets.Endocrinology. 2003; 144: 3774-3778Crossref PubMed Scopus (97) Google Scholar, Louis et al., 2010Louis G.W. Leinninger G.M. Rhodes C.J. Myers Jr., M.G. Direct innervation and modulation of orexin neurons by lateral hypothalamic LepRb neurons.J. Neurosci. 2010; 30: 11278-11287Crossref PubMed Scopus (83) Google Scholar, Yamanaka et al., 2003Yamanaka A. Beuckmann C.T. Willie J.T. Hara J. Tsujino N. Mieda M. Tominaga M. Yagami K. Sugiyama F. Goto K. et al.Hypothalamic orexin neurons regulate arousal according to energy balance in mice.Neuron. 2003; 38: 701-713Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar) that regulate locomotor activity and alertness and play a crucial role in energy balance and leptin action (Yamanaka et al., 2003Yamanaka A. Beuckmann C.T. Willie J.T. Hara J. Tsujino N. Mieda M. Tominaga M. Yagami K. Sugiyama F. Goto K. et al.Hypothalamic orexin neurons regulate arousal according to energy balance in mice.Neuron. 2003; 38: 701-713Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar, Funato et al., 2009Funato H. Tsai A.L. Willie J.T. Kisanuki Y. Williams S.C. Sakurai T. Yanagisawa M. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity.Cell Metab. 2009; 9: 64-76Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar). The mesolimbic DA system also contributes to the regulation of locomotor activity, feeding, and body weight, and this system is regulated, in part, by leptin and OX neurons (Fulton et al., 2006Fulton S. Pissios P. Manchon R.P. Stiles L. Frank L. Pothos E.N. Maratos-Flier E. Flier J.S. Leptin regulation of the mesoaccumbens dopamine pathway.Neuron. 2006; 51: 811-822Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar, Hommel et al., 2006Hommel J.D. Trinko R. Sears R.M. Georgescu D. Liu Z.W. Gao X.B. Thurmon J.J. Marinelli M. DiLeone R.J. Leptin receptor signaling in midbrain dopamine neurons regulates feeding.Neuron. 2006; 51: 801-810Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar, Leinninger et al., 2009Leinninger G.M. Jo Y.H. Leshan R.L. Louis G.W. Yang H. Barrera J.G. Wilson H. Opland D.M. Faouzi M.A. Gong Y. et al.Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.Cell Metab. 2009; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, Farooqi et al., 2007Farooqi I.S. Bullmore E. Keogh J. Gillard J. O'Rahilly S. Fletcher P.C. Leptin regulates striatal regions and human eating behavior.Science. 2007; 317: 1355Crossref PubMed Scopus (419) Google Scholar, Fadel and Deutch, 2002Fadel J. Deutch A.Y. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area.Neuroscience. 2002; 111: 379-387Crossref PubMed Scopus (392) Google Scholar, Figlewicz et al., 2007Figlewicz D.P. MacDonald N.A. Sipols A.J. Modulation of food reward by adiposity signals.Physiol. Behav. 2007; 91: 473-478Crossref PubMed Scopus (104) Google Scholar, Fulton et al., 2000Fulton S. Woodside B. Shizgal P. Modulation of brain reward circuitry by leptin.Science. 2000; 287: 125-128Crossref PubMed Scopus (330) Google Scholar, Perry et al., 2010Perry M.L. Leinninger G.M. Chen R. Luderman K.D. Yang H. Gnegy M.E. Myers Jr., M.G. Kennedy R.T. Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of Sprague-Dawley rats.J. Neurochem. 2010; 114: 666-674Crossref PubMed Scopus (38) Google Scholar). The mechanisms by which leptin regulates OX and the mesolimbic DA system remain poorly understood, however. Here, we address the role for physiologic leptin action via a subpopulation of LepRb neurons that contain the neuropeptide neurotensin (Nts), by generating and studying mice null for leptin action on these neurons. The lack of markers specific to many populations of LepRb neurons in the brain has limited the ability to genetically analyze their functions. Nts has an anatomic distribution similar to LepRb (Jennes et al., 1982Jennes L. Stumpf W.E. Kalivas P.W. Neurotensin: topographical distribution in rat brain by immunohistochemistry.J. Comp. Neurol. 1982; 210: 211-224Crossref PubMed Scopus (481) Google Scholar, Paxinos and Franklin, 2001Paxinos G. Franklin B. The Mouse Brain in Stereotaxic Coordinates.Second Edition. Academic Press, San Diego2001Google Scholar, Leinninger et al., 2009Leinninger G.M. Jo Y.H. Leshan R.L. Louis G.W. Yang H. Barrera J.G. Wilson H. Opland D.M. Faouzi M.A. Gong Y. et al.Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.Cell Metab. 2009; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar) in the lateral hypothalamic area (LHA). To address whether LHA LepRb neurons express Nts, we utilized LepRbEGFP mice (in which enhanced green fluorescent protein [EGFP] is expressed in LepRb neurons (Leinninger et al., 2009Leinninger G.M. Jo Y.H. Leshan R.L. Louis G.W. Yang H. Barrera J.G. Wilson H. Opland D.M. Faouzi M.A. Gong Y. et al.Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.Cell Metab. 2009; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, Leshan et al., 2010Leshan R.L. Opland D.M. Louis G.W. Leinninger G.M. Patterson C.M. Rhodes C.J. Munzberg H. Myers Jr., M.G. Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala.J. Neurosci. 2010; 30: 5713-5723Crossref PubMed Scopus (92) Google Scholar, Patterson et al., 2011Patterson C.M. Leshan R.L. Jones J.C. Myers Jr., M.G. Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells.Brain Res. 2011; 1378: 18-28Crossref PubMed Scopus (100) Google Scholar) to examine the potential colocalization of Nts-immunoreactivity (-IR) with LepRb, detected as GFP-IR (Figures 1A and 1B ). This analysis revealed that many LHA LepRb neurons contain Nts-IR (LepRbNts neurons). While Nts-IR was detected in many brain regions, Nts-IR only colocalized with LepRb neurons in the LHA (see Figure S1 available with this article online, and data not shown). To permit the study of leptin action via LepRbNts neurons, we inserted an internal ribosome entry site (IRES) plus the coding sequences for cre recombinase into the 3′UTR of Nts in mice to promote Nts neuron-restricted cre expression (Ntscre) (Figure 1C). We bred Ntscre mice with Leprfl animals (McMinn et al., 2004McMinn J.E. Liu S.M. Dragatsis I. Dietrich P. Ludwig T. Eiden S. Chua Jr., S.C. An allelic series for the leptin receptor gene generated by CRE and FLP recombinase.Mamm. Genome. 2004; 15: 677-685Crossref PubMed Scopus (68) Google Scholar) to generate Ntscre;Leprfl/fl (Nts-LepRbKO) animals in which LepRb signaling is ablated from LHA LepRbNts neurons (Figure 1C). Some of the resulting Nts-LepRbKO and Ntscre animals were generated on the Rosa26-EGFP reporter strain (Nts-LepRbKOEGFP and NtsEGFP mice, respectively) to selectively express EGFP in Nts neurons (Nts-EGFP neurons). The analysis of EGFP expression in these animals revealed the expected broad distribution of Nts-EGFP neurons in the brain (data not shown), including a large population in the LHA (Figures 1D–1I). We examined the leptin-stimulated induction of phosphorylated signal transducer and activator-3 (pSTAT3; which reveals neurons containing functional LepRb) in EGFP-IR neurons of NtsEGFP and Nts-LepRbKOEGFP animals. Approximately 30% of LHA Nts-EGFP neurons in NtsEGFP animals contained leptin-stimulated pSTAT3-IR. Conversely, approximately 60% of LHA pSTAT3/LepRb neurons colabeled with Nts-EGFP; these represent LepRbNts neurons (Figure 1D). Few Nts-EGFP neurons containing pSTAT3 were detected outside of the LHA (Figures 1F and 1H and Figure S1). Thus, LepRbNts neurons represent a LHA-restricted subpopulation of LepRb neurons that presumably play a unique and heretofore uncharacterized role in leptin action. While leptin-stimulated pSTAT3 outside of the LHA was unaltered in Nts-LepRbKOEGFP mice compared to controls (Figures 1G and 1I), leptin-stimulated pSTAT3 in the LHA was dramatically reduced in Nts-LepRbKOEGFP mice, and pSTAT3-IR was absent from LHA Nts-EGFP neurons in these animals (Figure 1E). Thus, functional LepRb is specifically ablated from LHA LepRbNts neurons in Nts-LepRbKO mice. To understand the effect of leptin on the firing of LepRbNts neurons, we examined the electrophysiologic response to leptin in Nts-EGFP neurons immediately above the fornix, where LepRbNts neurons are concentrated, in NtsEGFP and Nts-LepRbKOEGFP animals (Figure 2). In NtsEGFP mice, leptin depolarized and increased the firing of 62% of LHA Nts-EGFP neurons (n = 8/13 neurons; Vm control −58.3 ± 3 mV, leptin −49.2 ± 3; p = 0.0003), while ∼20% of LHA Nts-EGFP neurons responded to leptin with a slow hyperpolarization (n = 3/13 neurons; Vm control −48.4 ± 2 mV, leptin −64.9 ± 2; p = 0.006) (Figures 2A–2C). In Nts-LepRbKOEGFP mice, however, leptin hyperpolarized all recorded LHA Nts-EGFP neurons (n = 6/6 neurons; control −47.0 ± 4 mV, leptin −54.4 ± 4; p = 0.007) (Figures 2D and 2E). These data suggest that leptin directly depolarizes LepRbNts neurons, while non-LepRb-expressing LHA Nts neurons are indirectly hyperpolarized by leptin; deletion of LepRb from LepRbNts neurons in Nts-LepRbKO mice abrogates the direct depolarizing response. To interrogate the contribution of LHA LepRbNts neurons to leptin action, we examined energy balance and other physiologic parameters in male Nts-LepRbKO mice and their littermate controls (Leprfl/fl). Nts-LepRbKO mice exhibited increased body weight compared to controls (Figure 3A ); this excess weight was due to increased adiposity (Figures 3B and 3C), while lean mass was slightly decreased as a proportion of body mass (Figure 3D). Consistent with their increased adiposity, Nts-LepRbKO mice also had increased circulating leptin levels (Figure 3E). Interestingly, while (as reported previously; Balthasar et al., 2004Balthasar N. Coppari R. McMinn J. Liu S.M. Lee C.E. Tang V. Kenny C.D. McGovern R.A. Chua Jr., S.C. Elmquist J.K. et al.Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.Neuron. 2004; 42: 983-991Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar, Dhillon et al., 2006Dhillon H. Zigman J.M. Ye C. Lee C.E. McGovern R.A. Tang V. Kenny C.D. Christiansen L.M. White R.D. Edelstein E.A. et al.Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.Neuron. 2006; 49: 191-203Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar) no differences were observed between Lepr+/+ and Leprfl/fl animals (data not shown), Ntscre/+ animals weighed slightly less and exhibited decreased adiposity relative to Nts+/+ controls, suggesting a tendency of the Ntscre allele to decrease body weight and adiposity (Table S1). Thus, the increased weight and adiposity of Nts-LepRbKO mice is more dramatic by this comparison, since these animals possess the weight-reducing Ntscre allele. Beyond body weight and adiposity, no additional effects of the Ntscre allele alone were detected in our analysis (Table S1). Thus, leptin action via LepRbNts neurons contributes to the control of energy balance in mice. Nts-LepRbKO mice exhibited slightly increased food intake at the youngest age studied, although this small difference was not detected in older animals, nor was it significant when normalized to body weight (Figure 3F and data not shown). Also, Nts-LepRbKO mice exhibited decreased VO2 normalized to body weight (although not on a per-animal basis [Figure S2]) compared to control mice, especially during the dark (active) cycle, and had reduced ambulatory activity across the light-dark cycle (Figures 4A and 4B ). In contrast, other aspects of leptin action, including measures of reproduction, growth, body temperature, and glucose homeostasis, were unperturbed in the Nts-LepRbKO mice (Table S2). Thus, leptin action via LepRbNts neurons participates in the regulation of energy balance in chow-fed animals via food intake and activity/energy expenditure but does not substantially control neuroendocrine function. To understand how LepRbNts neurons might modulate brain function, we interrogated the projections of LHA Nts neurons by stereotaxically injecting the cre-inducible Ad-iZ/EGFPf virus (Leinninger et al., 2009Leinninger G.M. Jo Y.H. Leshan R.L. Louis G.W. Yang H. Barrera J.G. Wilson H. Opland D.M. Faouzi M.A. Gong Y. et al.Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.Cell Metab. 2009; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, Leshan et al., 2010Leshan R.L. Opland D.M. Louis G.W. Leinninger G.M. Patterson C.M. Rhodes C.J. Munzberg H. Myers Jr., M.G. Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala.J. Neurosci. 2010; 30: 5713-5723Crossref PubMed Scopus (92) Google Scholar) into the LHA of Ntscre mice (Figure 5A ); this virus mediates the expression of farnesylated EGFP (EGFPf) in cre-containing neurons, revealing their neural projections. We found that LHA Nts neurons project locally within the LHA and caudally to the VTA (Figures 5B–5E). Since not all LHA Nts neurons contain LepRb, we examined the potential projection of LHA LepRbNts neurons to the VTA by combining retrograde tracing from intra-VTA fluorogold (FG) (Figure S4A) with immunohistochemical detection of Nts-EGFP and leptin-induced pSTAT3-IR in the LHA of NtsEGFP mice (Figures 5F–5I). This analysis revealed the accumulation of VTA-derived FG in EGFP-IR (Nts only) and EGFP+pSTAT3-IR (LepRbNts) neurons in the LHA. Thus, LHA Nts and LepRbNts neurons project to the VTA. We also interrogated whether LHA Nts neurons might project onto neurons within the LHA by injecting Ad-iN/WED (which mediates the cre-inducible expression of the trans-synaptic tracer, WGA [Louis et al., 2010Louis G.W. Leinninger G.M. Rhodes C.J. Myers Jr., M.G. Direct innervation and modulation of orexin neurons by lateral hypothalamic LepRb neurons.J. Neurosci. 2010; 30: 11278-11287Crossref PubMed Scopus (83) Google Scholar] [Figure 5A]) into the LHA of Ntscre mice (Figures 5J–5L, Figure S4B). In this case, we observed numerous WGA-containing LHA neurons. We did not observe any WGA in MCH neurons (Figures S4C–S4E), suggesting that LHA Nts neurons do not contact MCH neurons. By contrast, many of the WGA-containing LHA neurons contained OX-IR, suggesting that LHA Nts neurons lie in a neuronal pathway connected to OX neurons and might therefore modulate the function of OX neurons. Leptin regulates OX neurons in two distinct manners, increasing Ox mRNA expression while inhibiting the fasting-induced activity of OX neurons (as determined by c-fos expression), suggesting that diminution of ambient leptin during fasting represents a major signal to increase OX neuron activity (Diano et al., 2003Diano S. Horvath B. Urbanski H.F. Sotonyi P. Horvath T.L. Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets.Endocrinology. 2003; 144: 3774-3778Crossref PubMed Scopus (97) Google Scholar, Horvath and Gao, 2005Horvath T.L. Gao X.B. Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia.Cell Metab. 2005; 1: 279-286Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, Yamanaka et al., 2003Yamanaka A. Beuckmann C.T. Willie J.T. Hara J. Tsujino N. Mieda M. Tominaga M. Yagami K. Sugiyama F. Goto K. et al.Hypothalamic orexin neurons regulate arousal according to energy balance in mice.Neuron. 2003; 38: 701-713Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar). Thus, if LepRbNts neurons mediate important aspects of physiologic leptin action on OX neurons, fasting should not alter the activity of OX neurons of Nts-LepRbKO mice, since the absence of LepRb from the Nts neurons in these mice would prevent the Nts cells from detecting decreased circulating leptin. Indeed, while a 24 hr fast robustly increased c-fos in OX neurons in control animals, fasting failed to significantly change the expression of c-fos in OX neurons from Nts-LepRbKO mice (Figures 6A–6E and antibody controls in Figure S5). We also treated control and Nts-LepRbKO mice with vehicle or leptin for 24 hr and examined body weight and Ox mRNA expression (Figures 6F and 6G). While leptin reduced the weight of control animals during the 24 hr of treatment, the weight loss was blunted in Nts-LepRbKO mice (Figure 6F), consistent with the role for leptin action via LepRbNts neurons in regulation of body weight. Furthermore, while leptin increased Ox expression in control animals, this response was absent in Nts-LepRbKO animals (Figure 6G). Thus, leptin action via LepRbNts neurons controls Ox expression as well as the regulation of OX neuron activity. Overall, these data suggest a central role for LepRbNts neurons in the modulation of OX neurons by leptin and confirm their importance in energy balance. A variety of data suggest important roles for leptin in control of the mesolimbic DA system, including in the response to amphetamine (AMPH; which promotes the release of cellular DA stores via the synaptic dopamine transporter [DAT] (Figlewicz et al., 1998Figlewicz D.P. Patterson T.A. Johnson L.B. Zavosh A. Israel P.A. Szot P. Dopamine transporter mRNA is increased in the CNS of Zucker fatty (fa/fa) rats.Brain Res. Bull. 1998; 46: 199-202Crossref PubMed Scopus (40) Google Scholar, Fulton et al., 2006Fulton S. Pissios P. Manchon R.P. Stiles L. Frank L. Pothos E.N. Maratos-Flier E. Flier J.S. Leptin regulation of the mesoaccumbens dopamine pathway.Neuron. 2006; 51: 811-822Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar, Kahlig et al., 2005Kahlig K.M. Binda F. Khoshbouei H. Blakely R.D. McMahon D.G. Javitch J.A. Galli A. Amphetamine induces dopamine efflux through a dopamine transporter channel.Proc. Natl. Acad. Sci. USA. 2005; 102: 3495-3500Crossref PubMed Scopus (206) Google Scholar, Sulzer et al., 1995Sulzer D. Chen T.K. Lau Y.Y. Kristensen H. Rayport S. Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport.J. Neurosci. 1995; 15: 4102-4108Crossref PubMed Google Scholar). To determine whether physiologic leptin action via LepRbNts neurons modulates the mesolimbic DA system, we examined the locomotor response of Nts-LepRbKO and control mice to AMPH, as well as examining other parameters of mesolimbic DA function (Figure 7). Consistent with the decreased home cage activity of Nts-LepRbKO mice (Figure 4B), the initial activity of Nts-LepRbKO mice in the locomotor chamber was reduced over the first 60 min of observation, although this difference in activity was absent following a vehicle injection after 60 min in the chamber. AMPH (IP, 4 mg/kg) rapidly increased the locomotor activity of control mice, but this effect was blunted in Nts-LepRbKO mice (Figure 7A), suggesting a role for LepRbNts neurons in control of the mesolimbic DA system. We measured VTA Th expression and NAc DA content in Nts-LepRbKO mice to determine whether decreased mesolimbic DA might underlie the altered locomotor response to AMPH in these animals (" @default.
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