Role of the SCT-activated gut-brown fat-brain axis in the control of food intake

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The endocrine action of the gut hormone secretin, discovered 120 years ago, was initially thought to be restricted to the enteric system. Meanwhile, various effects of secretin in other organs have been reported. We identified the gut hormone as physiological mediator of meal-associated thermogenesis in brown adipose tissue (BAT). Prandial release of secretin stimulates BAT thermogenesis, which induces meal termination and thereby plays a role in the regulation of hunger and satiation demonstrating a regulatory function of BAT beyond its role as a mere catabolic heater organ. Secretin’s effect on food intake is dependent on functional BAT, namely UCP1. Vice versa, antibody-based neutralization of endogenous secretin results in an attenuated meal-induced rise of BAT temperature as well as increased food intake leading to the establishment of a gut-BAT-brain axis. This is contradictory to a previous study proposing that the anorexigenic action of secretin is mediated by central action of secretin in the brain via the secretin receptor on hypothalamic proopiomelanocortinergic neurons. We therefore aim to determine the relative contribution of central as well as direct effects of secretin in meal-associated BAT-thermogenesis and subsequent satiation by conditional knockout of the secretin receptor. This approach will enable us to compare the impact of cell-specific secretin receptor ablation either in BAT or in hypothalamic POMCergic neurons on parameters of feeding behaviour, energy balance, and obesity. Pertaining to the secretin-mediated BAT activation another essential piece of the picture related to the mechanism of communication from BAT to brain is missing. Revealing the afferent pathway of BAT-brain communication will complement the understanding of the gut-BAT-brain axis. In principle, the signalling can operate through three different mechanisms: Convective heat transfer from BAT to brain by blood circulation, neuronal transmission from BAT to brain and endocrine batokine signalling. Even though our data suggest heat transfer as a signal, complementary and redundant pathways often control physiological processes. In addition to heat transfer, several lines of evidence also point at the involvement of afferent sensory nerves and batokines. We here aim to decipher the involvement of these pathways. A role of secretin in BAT activation and in the control of food intake is also evident in humans. Secretin-mediated BAT activation is associated with increased satiation, delayed motivation to resume eating, and reduced central responses to appetizing food items. Thus, secretin affects the homeostatic and the hedonic regulation of food intake. While the homeostatic system responds to the depletion of energy stores, the hedonic system is driven by rewarding value of highly palatable foods. Therefore, we aim to deepen our understanding of the role of secretin in homeostatic- and hedonic-driven food intake.