1. Glial mechanisms orchestrating adipose tissue lipid metabolism and glucose homeostasis.

Neuronal processes that control food intake, body weight, adipose tissue lipid metabolism and glucose homeostasis have been extensively investigated. However, the roles played by non-neuronal glial cells such as astrocytes remain incompletely understood. We recently find that astrocytes in the hippocampus and hypothalamus control neuronal synaptic plasticity and feeding behavior respectively. It remains unclear whether and how astrocytes in both central and peripheral nervous system control adipocyte functions and glucose metabolism. To answer those questions, we will employ coordinated combined neuroscience methods and techniques including cell-type selective chemo/optogenetics, photometry, electrophysiology, adipose tissue lipid metabolism and glucose homeostasis assays, and transgenic mouse lines, which will give us both neuroanatomically and temporally specific access to deciphering previously unknown astrocyte-adipocyte interactions that modulate systemic and adipose tissue lipid metabolism and glucose homeostasis.

2. Neural circuit pathways that modulate feeding and adipose tissue lipid metabolism.

We recently find that synaptic strength at orexigenic agouti-related protein (AGRP) neurons in the arcuate nucleus of the hypothalamus (ARH) and their action potential firing rates were up-regulated in response to energy deficit such as food deprivation and to hunger hormone ghrelin, suggesting that synaptic strength integrated at orexigenic neurons plays crucial roles in the control of feeding and energy states by modulating neural activities. However, the neuron populations in the brain and neural circuits that control adipose tissue lipid metabolism remain incompletely examined. We will identify, characterize and manipulate those cell populations and neural circuits using cell-type specific chemo/optogenetics, photometry, single cell RT-qPCR and RNA-seq, neurochemical assays, and adipose tissue lipid metabolism assays.

3. Neural circuit mechanisms of obesity and diabetes-associated affective behaviors.

We are also interested in studying the interactions between energy states and affective behaviors such as anxiety and depression. Previous literature provides overwhelming evidence to indicate that obesity and diabetes are often comorbid with psychiatric disorders, representing major health concerns as their rates have been gradually increasing in the world. We recently observed anxious and depressive-like phenotypes in obesity and diabetic mouse models. However, the involved neuron populations and neuronal circuitry await identification.

Yang Y, Atasoy D, Su HH, Sternson SM (2011) Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell. 146(6):992-1003. PMID:21925320. Featured in Cell and Cell Metabolism.

Tian L, Yang Y, Wysocki LM, Arnold AC, Hu A, Ravichandran B, Sternson SM, Looger LL, Lavis LD (2012) Selective esterase-ester pair for targeting small molecules with cellular specificity. Proc Natl Acad Sci U S A. 109(13):4756-61. PMID:22411832. Featured in Faculty 1000Prime.

Yang L, Qi Y, Yang Y* (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Reports. 11(5):798-807 PMID: 25921535. Highlighted in Cell press.

Yang Y, Lee P, Sternson SM (2015) Cell type-specific pharmacology of NMDA receptors using masked MK801. eLife. 4. doi:10.7554/eLife.10206. PMID: 26359633.

Qi Y, Yang Y* (2015) Hunger States Control the Directions of Synaptic Plasticity via Switching Cell Type-Specific Subunits of NMDA Receptors. Journal of Neuroscience. 35(38):13171-82. PMID: 26400946.

Sweeney P, Yang Y* (2015) An excitatory ventral hippocampus to lateral septum circuit that suppresses feeding. Nature Communications. 6:10188. doi: 10.1038/ncomms10188. PMID: 26666960. Featured in Faculty 1000Prime.

Sweeney P, Levack R, Watters J, Xu Z, Yang Y* (2016) Caffeine increases food intake while reducing anxiety-related behaviors. Appetite. 101:171-177. PMID:26972351.

Sweeney P, Qi Y, Xu Z, Yang Y* (2016) Activation of hypothalamic astrocytes suppresses feeding without altering emotional states. GLIA. 64(12):2263-2273. PMID:27658520.

Sweeney P, Yang Y* (2016) An Inhibitory Septum to Lateral Hypothalamus Circuit That Suppresses Feeding. Journal of Neuroscience. 36(44):11185-11195. PMID:27807162. Featured Article.

Sweeney P, Li C, Yang Y* (2017) Appetite suppressive role of medial septal glutamatergic neurons. Proc Natl Acad Sci U S A. 114(52):13816-13821. PMID:29229861 Highlighted in Nature.

Sweeney P, Yang Y* (2017) Neural Circuit Mechanisms Underlying Emotional Regulation of Homeostatic Feeding. Trends Endocrinol Metab. 28(6):437-448. Review. PMID:28279562.

Sweeney P, O'Hara K, Xu Z, Yang Y* (2017) HFD-induced energy-states-dependent bidirectional control of anxiety levels in mice. Int J Obes. 41(8):1237-1245. PMID:28465604.

Li C, Hou Y, Zhang J, Sui G, Du X, Licinio J, Wong ML, Yang Y* (2019) AGRP neurons modulate fasting-induced anxiolytic effects. Translational Psychiatry. 9(1):111. PMID:30850579.

Qi Y, Si D, Zhu L, Qi Y, Wu Z, Chen D, Yang Y* (2020) High-fat diet-induced obesity affects alpha 7 nicotine acetylcholine receptor expressions in mouse lung myeloid cells. Scientific Reports. 10,18368. PMID:33110180.

Zhang J, Chen D, Sweeney P, Yang Y* (2020) An excitatory ventromedial hypothalamus to paraventricular thalamus circuit that suppresses food intake. Nature Communications. 11(1):6326. PMID:33303759.

Huang T, Guan F, Licinio J, Wong ML, Yang Y* (2021) Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors. Molecular Psychiatry. 26(12):7270-7279. PMID:34489531. Highlighted in AMUZA.

Zhang J, Hou Y, Du XL, Chen D, Sui G, Qi Y, Licinio J, Wong ML, Yang Y* (2021) ADORA1-driven brain-sympathetic neuro-adipose connections control body weight and adipose lipid metabolism. Molecular Psychiatry. 26(7):2805-2819. PMID:33067580.

Chen D, Qi Y, Zhang J, Yang Y* (2022) Deconstruction of a hypothalamic astrocyte-white adipocyte sympathetic axis that regulates lipolysis in mice. Nature Communications. 13(1):7536. PMID:36477150.

Qi Y, Wu Z, Chen D, Zhu L, Yang Y* (2023) A role of STING in obesity-induced lung inflammation. Int J Obes. (In press).

Liu SM, et al. (2023) The gut signals to AGRP expressing cells of the pituitary to control glucose homeostasis. J Clin Invest (Accepted for publication)

Media:

Research Highlights (AMUZA): Successful Wireless Fiber Photometry

Research Highlights in Nature: Appetite Drop Off After Brain Region Fires

CrossTalk (Cell Press): Eating and the brain: Glial cells enter the fray

Anxiety.org: Anxious? Drink coffee and focus on something

Upstate With Distinction: Neuroscience student explores link between emotion and appetite