Gina Leinninger, Ph.D.
The incidence of obesity-linked diabetes (type-2 diabetes) is increasing worldwide and has accordingly been termed “the diabesity epidemic.” Despite the prevalence of overweight and obesity there are no truly effective pharmacological treatments or cures. Additionally, homeostatic systems regulated by the brain oppose sustained weight loss. Thus, understanding how the brain regulates energy balance and weight is crucial to developing better therapeutics for treatment and prevention of obesity and obesity-linked disease.
The Leinninger Laboratory studies how neurons in the lateral hypothalamic area (LHA) contribute to energy balance and obesity. The LHA is crucial area of the brain for regulating feeding, drinking, sleep and locomotor behaviors that can directly affect weight. Indeed, LHA neurons regulate some of the same brain circuits that mediate reward sensing and addiction (i.e. dopamine neurons.) There are several populations of LHA neurons that differ in their expression of neuropeptides and where they project within the brain (including populations containing neurotensin, orexin, leptin receptor and others) suggesting that these neuronal populations control different aspects of metabolic sensing and physiological output behavior. The goal of our lab is to understand how discrete neuronal populations in the LHA contribute to energy balance and physiology as a whole. We utilize novel mouse models, state-of-the art neuronal tract tracing and neuronal regulation techniques to interrogate LHA neurons and their role in physiology. In particular we examine:
1. What populations of LHA neurons respond to various metabolic stimuli, such as adiposity signals, feeding signals, exercise, etc.?
2. What neurotransmitters and neural pathways are involved?
3. How do LHA neurons regulate motivated behaviors (feeding, drinking, movement etc.) that contribute to energy balance?
4. Can we alter signaling via LHA neurons to promote weight loss or alter physiology?
Collectively, determining how LHA neurons signal and regulate behaviors will increase our understanding of how the brain controls energy balance and the pathogenesis of obesity.
Patterson CM, Wong JM, Leinninger GM, Allison MB, Gonzalez IE, Jones JC, Kennedy RT and Myers MG Jr. (2015). VTA neurotensin signaling links the lateral hypothalamus to striatal dopamine efflux. Endocrinology 156(5): 1692-1700
Brown JA, Woodworth HL and Leinninger GM (2015). To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance. Frontiers in Systems Neuroscience 9:1-24
Goforth PB, Leinninger GM, Patterson CM, Satin LS and Myers MG Jr.. (2014). “Leptin Acts via Lateral Hypothalamic Area Neurotensin Neurons to Inhibit Orexin Neurons by Multiple GABA-Independent Mechanisms.” Journal of Neuroscience 34(34): 11405-11415.
Opland DM, Sutton AK, Woodworth HL, Brown AB, Bugescu R, Garcia A, Christensen L, Rhodes CJ, Myers Jr. MG and Leinninger GM, (2013). Loss of neurotensin receptor-1 disrupts the control of the mesolimbic DA system by leptin and promotes hedonic feeding and obesity. Molecular Metabolism 2(4): 423-434
Kempadoo KA, Tourino C, Cho SL, Francesco M, Leinninger GM, Stuber GD, Zhang F, Myers MG, Deisseroth K, de Lecea L and Bonci A (2013). “Hypothalamic Neurotensin Projections Promote Reward by Enhancing Glutamate Transmission in the VTA.” Journal of Neuroscience 33(18): 7618-7626
Leinninger GM, Opland DM, Jo Y-H, Faouzi M, Christensen L, Capellucci LA, Rhodes CJ, Gnegy ME, Becker JB, Pothos EN, Seasholtz AF, Thompson RC and Myers Jr. MG (2011). Leptin action via neurotensin neurons controls Orexin, the mesolimbic dopamine system and energy balance. Cell Metabolism 14: 313-323.
Grossberg AJ, Zhu XX, Leinninger GM, Levasseur PR, Braun TP, Myers MG Jr. and Marks DL (2011). Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. Journal of Neuroscience 31(31):11376-11386.
Lam DD*, Leinninger GM*, Louis GW, Garfield AS, Martson OJ, Leshan RL, Scheller EL, Christensen L, Donato J, Xia J, Evans ML, Elias C, Dalley JW, Burdakov D, Myers Jr. MG, and Heisler LK (2011). Leptin does not directly affect CNS serotonin neurons to influence appetite. Cell Metabolism 13(5): 584-91 *authors contributed equally to this work.
Leinninger GM (2011). Lateral thinking about leptin: a review of leptin action via the lateral hypothalamus. Physiol Behav 104: 572-581.
Louis G, Leinninger GM, Rhodes C and Myers Jr. MG (2010). Direct innervation and control of orexin neurons by lateral hypothalamic LepRb neurons. Journal of Neuroscience 30(34): 11278-87
Perry ML, Leinninger GM, Chen R, Luderman KD, Yang H, Gnegy ME, Myers Jr. MG and Kennedy R (2010). Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of Sprague-Dawley rats. Journal of Neurochemistry 114(3):666-74
Leshan RL, Opland DM, Louis GW, Leinninger GM, Patterson CM, Rhodes CJ, Munzberg H and Myers Jr., MG (2010). Ventral Tegmental Area Leptin Receptor Neurons Specifically Project to and Regulate Cocaine- and Ampehtamine-Regulated Transcript Neurons of the Extended Central Amygdala. Journal of Neuroscience 30(16): 5713-5723.
Leinninger GM, Jo Y-H, Leshan RL, Louis GW, Yang H, Barrera JG, Wilson H, Opland DM, Faouzi MA, Gong Y, Jones JC, Rhodes CJ, Chua Jr. S, Diano S, Horvath TL, Seeley RJ, Becker JB, Münzberg H, Myers Jr, MG (2009). Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metabolism, 10(2): 89-98.