Brown adipocyte mitochondria, equipped with UCP1, uncouple respiration from ATP synthesis by collapsing proton-motive force and thereby directly dissipate the chemical energy of fatty acids and glucose as heat. This energy wasting mechanism is constitutively suppressed by purine nucleotide binding to UCP1, but activated by free fatty acids. The canonical pathway stimulating brown fat thermogenesis requires activation of beta-adrenergic receptor signaling in brown adipocytes by the release of norepinephrine from sympathetic nerves innervating brown fat. Mimicking this pathway by a single injection of the beta-3-adrenergic receptor ligand CL316,243 not only activates brown fat thermogenesis, but also results in a pronounced inhibition of 24h food intake (1). Conversely, brown fat thermogenesis is activated during a meal (2). The role of meal-associated thermogenesis in brown fat and the underlying molecular mediator has been elusive (3). According to the thermoregulatory feeding hypothesis (4), we propose that brown fat thermogenesis plays a so far unappreciated role in the regulation of food intake (3). Ultradian cycles of brown fat activation may control meal initiation and termination. However, a major contribution of the sympathetic innervation as a mediator of such meal-associated cycles of thermogenesis is unlikely. Only carbohydrate rich meals activate the sympathetic nervous system, but all macronutrients elicit meal-associated thermogenesis. Beta-blockade with propranolol does not affect food intake, and propranolol treatment before a carbohydrate-rich meal does not attenuate meal-associated thermogenesis. Based on these observations, we screened for meal-associated signals derived from the gut that potentially activate oxygen consumption in brown adipocytes (3,5). Our transcriptome analysis in murine brown fat revealed a number of Gs-protein coupled receptors, of which the secretin receptor showed relatively abundant expression (3,5). In microplate respirometry assays of primary brown adipocytes, configured to quantify UCP1-dependent uncoupled respiration, the gut hormone secretin increased oxygen consumption to a comparable level as the beta-adrenergic receptor agonist isoproterenol. High respiration rates induced by secretin, alike isoproterenol, were dependent on cAMP-PKA mediated activation of lipolysis, and absent in brown adipocytes from Ucp1-KO mice. siRNA mediated knockdown of the secretin receptor diminished secretin-induced respiration. Thus, the gut hormone secretin is a novel non-adrenergic activator of UCP1-dependent thermogenesis in brown adipocytes. In vivo experiments with mice demonstrated that a single injection of secretin increases whole body resting metabolic rate and inhibits food intake in wildtype, but not in Ucp1-KO mice. Notably, secretin treatment decreased Agrp mRNA, and increased Pomc and Trpv1 mRNA levels in the hypothalamus of wildtype, but not Ucp1-KO mice. Notably, the meal-associated rise in brown fat temperature was regularly followed by termination of feeding. Comparing feeding behavior in wildtype and Ucp1-KO mice, the latter had fewer, but larger meals. Blocking endogenous secretin with a neutralizing antibody attenuated brown fat thermogenesis during refeeding, and increased food intake of mice. Propranolol pretreatment efficiently attenuated the thermogenic action of the beta-3-adrenergic agonist, CL316,243, but did not inhibit the effects of secretin on brown fat thermogenesis and food intake. Our results reveal the gut hormone secretin as the endocrine mediator of meal-associated thermogenesis in brown fat. The meal-induced rise of secretin levels in the blood circulation causes direct activation of brown fat. We hypothesize that the resulting rise in brain temperature conveys information on feeding status to the brain and promotes satiation. Thus, secretin triggers a so far unknown endocrine communication axis from the gut via brown fat to the brain which functions to control food intake (3). Pertaining to the role of brown fat as a heater organ in mammalian energy balance, the physiological role of this endocrine axis in the control of energy intake deserves more attention.