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The physiological mechanisms underlying BCAA regulation are poorly understood. Here we show that insulin signaling in the mediobasal hypothalamus (MBH) of rats is mandatory for lowering plasma BCAAs, most probably by inducing hepatic BCAA catabolism. Insulin receptor deletion only in agouti-related protein (AgRP)\u2013expressing neurons (AgRP neurons) in the MBH impaired hepatic BCAA breakdown and suppression of plasma BCAAs during hyperinsulinemic clamps in mice. In support of this, chemogenetic stimulation of AgRP neurons in the absence of food significantly raised plasma BCAAs and impaired hepatic BCAA degradation. A prolonged fasting or ghrelin treatment recapitulated designer receptors exclusively activated by designer drugs\u2013induced activation of AgRP neurons and increased plasma BCAAs. Acute stimulation of vagal motor neurons in the dorsal motor nucleus was sufficient to decrease plasma BCAAs. Notably, elevated plasma BCAAs were associated with impaired glucose homeostasis. These findings suggest a critical role of insulin signaling in AgRP neurons for BCAA regulation and raise the possibility that this control may be mediated primarily via vagal outflow. Furthermore, our results provide an opportunity to closely examine the potential mechanistic link between central nervous system\u2013driven BCAA control and glucose homeostasis.<\/jats:p>","DOI":"10.2337\/db20-0510","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T01:05:19Z","timestamp":1603933519000},"page":"62-75","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":15,"title":["Central Regulation of Branched-Chain Amino Acids Is Mediated by AgRP Neurons"],"prefix":"10.2337","volume":"70","author":[{"given":"Ritchel B.","family":"Gannaban","sequence":"first","affiliation":[{"name":"Neurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cherl","family":"NamKoong","sequence":"additional","affiliation":[{"name":"Division of Functional 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