NTS Catecholamine Neurons Mediate Hypoglycemic Hunger via Medial Hypothalamic Feeding Pathways

• Published in: Cell metabolism 2020-02, Vol.31 (2), p.313-326.e5
• Main Authors: Aklan, Iltan, Sayar Atasoy, Nilufer, Yavuz, Yavuz, Ates, Tayfun, Coban, Ilknur, Koksalar, Fulya, Filiz, Gizem, Topcu, Iskalen Cansu, Oncul, Merve, Dilsiz, Pelin, Cebecioglu, Utku, Alp, Muhammed Ikbal, Yilmaz, Bayram, Davis, Deborah R., Hajdukiewicz, Karolina, Saito, Kenji, Konopka, Witold, Cui, Huxing, Atasoy, Deniz
• Format: Article
• Language: English
• Subjects: Agouti-Related Protein - metabolism; AgRP; Animals; Appetite Regulation; arcuate nucleus; catecholamine; feeding; Female; hypoglycemia; Hypoglycemia - metabolism; hypoglycemic unawareness; Hypothalamus - cytology; Hypothalamus - metabolism; Male; Mice; Mice, Inbred C57BL; Neurons - cytology; Neurons - metabolism; norepinephrine; NTS; Solitary Nucleus - cytology; Solitary Nucleus - metabolism; tyrosine hydroxylase
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.11.016

Glucose is the essential energy source for the brain, whose deficit, triggered by energy deprivation or therapeutic agents, can be fatal. Increased appetite is the key behavioral defense against hypoglycemia; however, the central pathways involved are not well understood. Here, we describe a glucoprivic feeding pathway by tyrosine hydroxylase (TH)-expressing neurons from nucleus of solitary tract (NTS), which project densely to the hypothalamus and elicit feeding through bidirectional adrenergic modulation of agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons. Acute chemogenetic inhibition of arcuate nucleus (ARC)-projecting NTSTH neurons or their target, AgRP neurons, impaired glucoprivic feeding induced by 2-Deoxy-D-glucose (2DG) injection. Neuroanatomical tracing results suggested that ARC-projecting orexigenic NTSTH neurons are largely distinct from neighboring catecholamine neurons projecting to parabrachial nucleus (PBN) that promotes satiety. Collectively, we describe a circuit organization in which an ascending pathway from brainstem stimulates appetite through key hunger neurons in the hypothalamus in response to hypoglycemia. [Display omitted] •NTSTH axons innervate the ARC and elicit food intake via norepinephrine release•ARC-projecting NTSTH neurons are required for glucoprivic feeding•AgRP neurons are targeted by NTSTH axons and contribute to glucoprivic feeding•ARC- and PBN-projecting NTSTH neurons are largely distinct Increased appetite is a key line of defense against hypoglycemia. Aklan et al. have identified an ascending pathway from the brainstem to the hypothalamus that is required for hypoglycemia-induced food intake.