Brown Fat Starts Heating and Terminates Eating
What Is this Brown Fat and Why Does Everyone Want it?
- Fig. 1: Secretin-induced signaling cascade in brown adipocytes. The activation of the Gs-protein coupled secretin receptor (SCTR: secretin receptor) by secretin leads to the activation of adenylyl cyclase (AC) and thus to an increase of intracellular cAMP (cyclic adenosine monophosphate). This in turn leads to the activation of proteinkinase A (PKA). The lipases HSL and ATGL (hormone sensitive lipase and adipocyte triglyceride lipase) are also activated, leading to lipolysis and thus to the release of free fatty acids (FFA). In the mitochondria, these are used both as fuel and as activators for the uncoupling protein 1 (UCP1). Uncoupling of oxygen consumption from the production of the energy equivalent ATP leads to heat generation.
- Fig. 2: Secretin-induced meal-associated thermogenesis of brown adipose tissue mediates satiation.
When we talk about adipose tissue in the human body, we usually mean white adipose tissue. In comparison to white adipose tissue, which serves as a storage for excessive calories in the form of energy-rich triglycerides, brown adipose tissue (BAT) produces heat when exposed to cold. Whenever a cold stimulus is registered by the brain, the neurotransmitter noradrenaline is released by the sympathetic nervous system, which in turn activates its receptors in brown adipose tissue and thus activates a signaling cascade that turns on fat breakdown (lipolysis). The resulting free fatty acids within the fat cell (adipocyte) serve in the mitochondria both as fuel and as activators of uncoupling protein 1 (UCP1). Once UCP1, a protein found exclusively in brown adipocytes, is activated, the chemical energy of the nutrients is directly converted into heat and not used for the production of the energy equivalent ATP, which is the universal and direct energy carrier of the cells and provides energy for mechanical, chemical or osmotic work.
Energy is “wasted” and heat is generated. This is the so-called non-shivering thermogenesis, which plays beside the muscle shivering an important role in thermoregulation. For a long time researchers believed that, this heating organ is only present in newborns, small mammals and hibernators to maintain body temperature. The discovery that brown adipose tissue is not only present in adults, but can also be activated has reopened the field of brown fat research. It aroused particular interest in obesity research, as activated brown fat increases energy expenditure.
It is therefore even more exciting that brown adipose tissue was already associated with so-called meal-associated thermogenesis almost 40 years ago. The concept of thermoregulatory feeding states that heat generation as a result of food intake could serve as a feedback signal for satiety. In fact, an increase of BAT temperature of about two degrees Celsius could be observed in fasted mice after refeeding. Contrary to the general opinion of experts that meal-associated activation of brown fat occurs via the sympathetic nervous system in the same way as that caused by cold, the use of a beta-blocker has now shown that it must take place via an unknown factor independent of the sympathetic nervous system.
In short: Brown fat is activated after eating, but not via the brain.
The Gut Hormone “Secretin”
In the search for the molecular mediator of meal-associated thermogenesis, an endocrine gastrointestinal factor, meaning a messenger substance that is released from the gastrointestinal tract after food intake and reaches the target cells via the blood, appeared most likely. Therefore, the presence of receptors for gastrointestinal peptide hormones was analyzed in BAT. The secretin receptor stood out due to its comparatively high expression.
Acidification of the duodenum is the primary stimulus for the release of secretin from the enteroendocrine S-cells of the duodenum. This means that as soon as the acidic food mash from the stomach reaches the small intestine, secretin is released into the bloodstream. Once in circulation, it exerts pleiotropic effects. Among other things, it stimulates the bicarbonate and water secretion of the pancreas and is involved in the regulation of gastric acid secretion and gastric motility. Furthermore, lipolytic effects in white adipose tissue have been described in the literature, which is a prerequisite for the activation of UCP1 in brown adipocytes. Although secretin was discovered by Bayliss and Starling already in 1902, relatively little is known about this peptide hormone. In this study the effect of secretin on BAT thermogenesis as well as the involvement of brown fat and its interaction with secretin in relation to meal-associated thermogenesis should be investigated. In vitro experiments to analyze the effects of secretin on brown adipocytes showed that the intestinal hormone increases oxygen consumption of brown adipocytes in a UCP1-dependent manner, meaning it activates brown adipocytes. Detailed investigations showed that secretin initiates the same signaling cascade by activating the secretin receptor as noradrenaline from the sympathetic nervous system (Fig. 1).
Secretin Increases Energy Expenditure
As already described, this mechanism leads to an increase in energy expenditure, which can be determined in vivo by indirect calorimetry. The amount of oxygen and carbon dioxide that an organism consumes or produces is measured and the energy expenditure is then calculated. In the described investigations, a secretin injection not only led to an increase in oxygen consumption and thus to an increased energy expenditure, but also to an increase in the temperature of the interscapular (= located between the shoulder blades) brown adipose tissue depot in mice. Since this phenomenon was not observed in mice with defective brown adipose tissue (so-called UCP1 knockout mice), it could be concluded that secretin increases energy turnover by activating brown fat.
Secretin-induced Brown Fat Thermogenesis Leads to Satiation
Secretin’s role in meal-associated thermogenesis has been demonstrated by the use of UCP1 knockout mice and antibody-based blocking of endogenous secretin activity. On the one hand, reduced food intake was observed in fasted mice after secretin injection. However, this inhibitory effect did not occur in UCP1 knockout mice. Whenever secretin activity was blocked with the antibody, the mice ate more and showed a lower increase in BAT temperature. In summary, this means that food intake leads to the release of secretin, which activates thermogenesis of brown adipose tissue. This activation of brown fat is then sensed in the brain. Three different ways of communication are possible. A rise in brain temperature could alter signaling in the brain, afferent nerve pathways from brown fat to the brain could pass on the information or special messengers of brown fat, so-called BATokines, could reach the brain via the blood and thus pass on the information. Since an injection of secretin alone leads to an altered gene expression of appetite-suppressing and appetite-increasing peptides in the hypothalamus, but this effect was not observed in mice with a defective heating organ, heat generation seems to be the most plausible possibility at present. Once attained in the brain, the information is centrally integrated and meal termination or satiation occurs (Fig. 2).
This regulatory mechanism and the importance of both secretin and the activation of brown fat thermogenesis in the regulation of satiation could be substantiated by a high-resolution analysis of the feeding behavior of mice. As soon as one of the two contributors (secretin or BAT) was manipulated, the mice showed no increased absolute energy intake, but a clearly changed pattern in eating behavior, characterized among other things by larger and longer meals, but at the same time reduced meal frequencies. Interestingly, a further investigation of nearly 2000 mouse meals revealed that every single meal is followed by an increase in BAT temperature and that the meal is terminated when a certain threshold temperature is reached. This means that both secretin and brown fat play a key role in regulating satiation, but one must differentiate between acute or short-term satiation and long-term satiety. Secretin-induced thermogenesis is not a tool for manipulating absolute energy intake; rather, it could be used to reduce meal sizes.
From Mouse to Human
A PET-CT analysis of 15 young men showed that secretin increases glucose uptake into brown adipose tissue. New results give first indications of a satiation effect of secretin also in humans. The function of brown fat as a mediator of satiation discovered in mice could therefore also be present in humans. Optimizing the secretin release during a meal could trigger a premature feeling of satiation and thus limit calorie intake. Thus, it is quite conceivable that our choice of certain foods naturally stimulates the secretin production, which leads to a stronger activation of brown fat and we become full faster. Which nutrients come into consideration here is subject of further studies.
In conclusion, it is important to note that research on brown fat in the field of obesity and diabetes is of particular importance regarding the fact that the metabolic activity of the heating organ decreases with age and with increasing BMI. Active brown adipose tissue not only increases energy expenditure, but also leads to satiation and thus reduces energy intake. That means, it manipulates both sides of the energy balance.
Katharina Schnabl1 und Martin Klingenspor1
1 Wissenschaftszentrum Weihenstephan-Lehrstuhl für molekulare Ernährungsmedizin, Else Kröner Fresenius Zentrum für Ernährungsmedizin-TU Munich, Freising, Germany
Wissenschaftszentrum Weihenstephan-Lehrstuhl für molekulare Ernährungsmedizin
Else Kröner Fresenius Zentrum für Ernährungsmedizin-TU Munich
Yongguo Li*, Katharina Schnabl*, Sarah-Madeleine Gabler, Monja Willershäuser, Josefine Reber, Angelos Karlas, Sanna Laurila, Minna Lahesmaa, Mueez u Din, Andrea Bast-Habersbrunner, Kirsi A. Virtanen, Tobias Fromme, Florian Bolze, Libbey S. O’Farrell, Jorge Alsina-Fernandez, Tamer Coskun, Vasilis Ntziachristos, Pirjo Nuutila, and Martin Klingenspor: Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation, Cell (November 2018) DOI: 10.1016/j.cell.2018.10.016 * These authors contributed equally