Cheng et al., 2011 Cheng C.Y.

Chu J.Y.

Chow B.K. Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system.

Abrams and Hammel, 1964 Abrams R.

Hammel H.T. Hypothalamic temperature in unanesthetized albino rats during feeding and sleeping.

Blessing et al., 2013 Blessing W.

Mohammed M.

Ootsuka Y. Brown adipose tissue thermogenesis, the basic rest-activity cycle, meal initiation, and bodily homeostasis in rats.

Jeong et al., 2018 Jeong J.H.

Lee D.K.

Liu S.M.

Chua Jr., S.C.

Schwartz G.J.

Jo Y.H. Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake.

Bartness et al., 2010 Bartness T.J.

Vaughan C.H.

Song C.K. Sympathetic and sensory innervation of brown adipose tissue.

Ryu et al., 2015 Ryu V.

Garretson J.T.

Liu Y.

Vaughan C.H.

Bartness T.J. Brown adipose tissue has sympathetic-sensory feedback circuits.

Chu et al., 2013 Chu J.Y.

Cheng C.Y.

Sekar R.

Chow B.K. Vagal afferent mediates the anorectic effect of peripheral secretin.

Gut hormones play a critical role in relaying signals of nutritional and energy status from the gut to the central nervous system in order to regulate food intake. Canonically, satiation signals reach the brain either directly via the blood (e.g., amylin and ghrelin) or indirectly by activation of vagal afferent nerves in the intestine (e.g., CCK and GLP-1). In our study, the common satiating effect evoked by secretin and CL indicates that meal termination by BAT-derived heat production is another alternative general mechanism. The hypothalamus and brainstem harbor metabolic sensors, which play a central role in the control of hunger and satiation. Therefore, the meal-termination signal that encodes the nutritional status must be relayed from BAT to the brain. Consistent with this notion, secretin treatment increases anorectic neuropeptide expression in hypothalamic nuclei (). Our study further demonstrated that the modulatory effects of secretin on feeding-related neuropeptides were UCP1 dependent, consolidating the essential role of BAT thermogenesis in mediating the satiation effect of secretin. Regarding communication between BAT and said brain regions, it is most likely that a rise in local brain temperature caused by BAT thermogenesis represents the key signal inducing satiation. This view is supported by a classical study demonstrating a rise in temperature in the preoptic hypothalamic area during feeding in rats, where a strong positive correlation was found between the maximal temperature rise in the hypothalamus and the duration of feeding (). And there is further evidence that BAT thermogenesis contributes to increases in body and brain temperature under ad libitum condition (). A very recent report found a subpopulation of POMC neurons expressing the temperature-sensitive ion channel, TRPV1, which can directly sense local changes in brain temperature. Slight increases in body temperature in response to exercise caused a TRPV1-dependent increase in the activity of POMC neurons, which suppressed feeding in mice (). Consistent with this scenario, we discovered that secretin treatment altered Trpv1 transcript abundance in the hypothalamus of WT but not UCP1-KO mice. Despite our data indicating heat as a signal, other possibilities such as neuronal or endocrine mechanisms cannot be excluded. Secretin-induced release of adipokines (batokines) or neuronal afferent signaling may alter melanocortin signaling in the hypothalamus. In fact, it has been postulated that afferent sensory nerves in BAT sense the thermal status, blood flow, or intracellular lipolytic products and hence regulate BAT thermogenesis via efferent SNS output (). Of note, several hypothalamic nuclei such as the paraventricular nucleus, dorsomedial hypothalamus, and lateral hypothalamus receive sensory inputs from fat depots, pointing toward a sensory feedback mechanism (). This alternative or complementary pathway of BAT-brain communication along the gut-secretin-BAT-brain axis is supported by the observation that the anorexigenic action of secretin depends on afferent sensory nerves (). Further studies are warranted to dissect the contributions of these potential mechanisms. In any case, demonstration of a non-canonical role of BAT in relaying nutritional status to brain beyond the canonical gut-vagal nerve-brain axis uncovers a yet unknown facet of the complex regulatory system that contributes to the termination of feeding.