Secretin Links Brown Fat to Food Intake: New Perspectives for Targeting Energy Balance in Humans

Abstract

In 1902, Neumann referred to the concept of Luxuskonsumption in his habilitation thesis, essentially stating that we can dissipate excess nutritional energy as heat to keep slim: "On the other hand, we also know very well that someone who otherwise 'lives well' consumes a sufficient amount of food and in the process enters into a luxury consumption in the organism" (1)*. Sixty years later, the thermogenic function of brown fat was first recognized, leading to significant research efforts to address the role of the sympathetic nervous system for cold-and diet-induced thermogenesis in brown fat. Recruitment and activation of brown fat thermogenesis was envisioned as a feasible strategy to promote negative energy balance and lose weight. In retrospect, research targeting brown fat for obesity therapy has been characterized by phases of skepticism and enthusiasm, with the latter currently prevailing (2). To date, however, it remains unclear whether sufficient brown fat capacity for energy expenditure can be recruited in people with obesity to reduce body weight effectively (3). In the positive case, this would require that increased brown fat thermogenesis is not fully compensated by increasing food intake (4). Ten years ago, landmark publications reported on the presence of cold-inducible brown fat in human adults (5). Cold-inducible activation of human brown fat is impaired with age and in people with obesity and type 2 diabetes, whereas cold acclimation initiates remission in association with improved metabolic homeostasis. In principle, given the current estimate of more than 300 g, total brown fat mass in humans could significantly promote negative energy balance if permanently active (6). Our lifestyle in thermoneutral environments, however, normally precludes cold-induced brown fat activation.Other than cold-induced thermogenesis, resting metabolic rate is also increased in association with a meal, known as the thermal effect of food. This effect is partially due to the obligatory costs of digestion and resorption, which depend on the macronutrient composition and caloric density of meals. However, as a facultative component, brown fat is also activated during meal ingestion. A recent study demonstrated that a single mixed meal activates human brown fat to the same degree as cold exposure (7). While obligatory costs of food digestion and resorption are inevitable, the reason for meal-associated thermogenesis in brown fat remains unclear. In this context, previous research pointing at a role of brown fat in the control of food intake may provide an answer. The hypothetical framework of thermoregulatory feeding implies that episodic events of brown fat activation are responsible for meal initiation and termination (8). The drop of core body temperature during a nonfeeding interval eventually triggers a burst of sympathetic nerve activity, stimulating brown fat thermogenesis. Concomitant glucose uptake into brown fat from the circulation results in hypoglycemia, which is sensed in the brain and initiates feeding....

The gut hormone secretin triggers a gut–brown fat–brain axis in the control of food intake

“…Alternatively, the prandial surge of endogenous secretin could be boosted in a timely manner to promote satiation. Secretagogues or cleavage‐inhibitors of secretin may efficiently accelerate meal termination and thereby reduce caloric intake by increasing the yield of prandial secretin (Klingenspor, 2019). Since duodenal acidification is the primary stimulus for secretin release from S‐cells in the epithelium of the duodenum into the circulation, meal composition could also be a crucial determinant for secretin release and subsequent brown fat activation.…”