Leptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding

Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Cell metabolism (Impact Factor: 17.57). 09/2009; 10(2):89-98. DOI: 10.1016/j.cmet.2009.06.011
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The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system.

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    • " do not respond . The reason for these differential effects of leptin on LHA GABAergic neurons is unknown ( Leinninger et al . , 2009 ) . Nevertheless , ablation of leptin receptors from LHA GABAergic neurons that project to the VTA specifically decreases mesolimbic DA release and contributes to the development of obesity ( Fulton et al . , 2006 ; Leinninger et al . , 2009 ) . Feeding peptides can also directly modulate the activity of mesolimbic DA neurons . For example , DA neurons in the VTA express receptors to leptin ( Hommel et al . , 2006 ) , ghrelin , insulin , orexin , melanocortin and GLP - 1 ( Narayanan et al . , 2010 ; Dossat et al . , 2011 ; Dossat et al . , 2013 ) . Furthermore , orexigenic "
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    04/2015; 10(2). DOI:10.1007/s11515-015-1348-0
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    • "Moreover, deletion of leptin receptors in both Pomc and VMH neurons resulted in an additive effect on body weight. Among other examples, leptin receptors on GABAergic neurons of the lateral hypothalamic area (LHA) modulate the mesolimbic dopaminergic system and decrease feeding (Leinninger et al., 2009). Also, deficiency of leptin receptors in a brainstem site called the dorsal vagal complex causes hyperphagia, resulting in modest weight gain (Scott et al., 2011; Skibicka and Grill, 2009). "
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    Cell 03/2015; 161(1):133-145. DOI:10.1016/j.cell.2015.02.023 · 32.24 Impact Factor
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    • "Composition of LH Input to the VTA We show that in addition to a glutamatergic LH-VTA component (Kempadoo et al., 2013), there is also a significant GABAergic component in the projection (Leinninger et al., 2009), and that LH neurons synapse directly onto both DA and GABA neurons in the VTA (Figure 6). However, there is a difference in the balance of the excitatory/inhibitory input onto VTA DA and GABA neurons. "
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