Central and nutritional control of adaptive thermogenesis

Adaptive thermogenesis is under central control. Exposure to cold and diet is detected by the brain, resulting in the activation of efferent pathways controlling energy dissipation. The SNS, which heavily innervates thermo-genic targets such as BAT and skeletal muscle, appears to be the main effector of this response (reviewed in references 4 and 42). The sympatho-adrenergic control of BAT thermogenesis is well understood (Fig. 4.2). In BAT, the noradrenaline released by the activated SNS endings interacts with P-adrenoceptors on the brown adipocyte cell membrane promoting lipolysis of the stored triacylglycerols and mitochondrial oxidation of the released fatty acids to fuel thermogenesis, UCP1 synthesis and activity, and tissue recruitment (reviewed in references 5 and 43).

The brain also affects energy expenditure by means of the hypotha-lamic-pituitary-thyroid axis. The mechanism by which thyroid hormone stimulates thermogenesis is not established, but it seems to be due to multiple effects on various aspects of energy metabolism such as substrate cycling, ion cycling and mitochondrial proton leaks.44 Thyroid hormone levels seem not to be modulated during cold exposure or consumption of high-calorie diets, but they do drop during starvation, and this may contribute to starvation-induced decreases in thermogenesis (see reference 4).

Signals involved in the long-term regulation of energy balance that convey information to the brain about the size of body fat stores (the so-called 'adiposity signals'), besides affecting food intake, modulate energy expenditure through effects on the activity of the SNS and the pituitary-thyroid axis, and also through direct effects on the oxidative and thermo-genic capacity/activity of peripheral tissues. This is the case for leptin, the paradigm of the adiposity signal, which suppresses appetite, and enhances energy expenditure and fat oxidation in peripheral tissues (reviewed in reference 45). In human obesity, leptin deficiency is rare, but leptin resistance is common.

Although feeding in general stimulates thermogenesis, not all macronu-trients are equally effective in triggering this response. The thermic effect of protein is 20-35% of energy consumed, and this number falls to 5-15% for carbohydrates; the thermic effect associated with fat is generally even lower than that associated with carbohydrate (see reference 46). The differences are attributed mainly to the fixed component of the thermic effect

Female Male Zone Adrenal

Fig. 4.2 Adrenergic control of BAT thermogenesis. Noradrenaline (NA) released by the activated SNS acts on P-adrenoceptors, primarily the P3, which are coupled to adenylyl cyclase (AC) through stimulatory G proteins, and thus stimulates the generation of cAMP, which in turn activates protein kinase A (PKA). PKA catalyzes the phosphorylation of cAMP regulatory element binding protein (CREB), which leads to increased ucp1 gene expression. PKA also catalyzes the phosphorylation of hormone sensitive lipase (HSL) and perilipin (the protein that covers the intra-cellular lipid droplets) triggering activation of the former and dissociation of the latter from the lipid droplets, thus activating lipolysis of triacylglycerol (TG) stores. Released fatty acids (FA) are channeled to the mitochondria where they enter the P-oxidation pathway and then the citric acid cycle, leading to the formation of reduced electron carriers (FADH2 and NADH) which are then oxidized by the respiratory chain. UCP1 dissipates the proton gradient generated by the respiratory chain, leading to a release of energy as heat (thermogenesis). CM, chylomicrons;

VLDL, very low density lipoproteins; LPL, lipoprotein lipase.

Fig. 4.2 Adrenergic control of BAT thermogenesis. Noradrenaline (NA) released by the activated SNS acts on P-adrenoceptors, primarily the P3, which are coupled to adenylyl cyclase (AC) through stimulatory G proteins, and thus stimulates the generation of cAMP, which in turn activates protein kinase A (PKA). PKA catalyzes the phosphorylation of cAMP regulatory element binding protein (CREB), which leads to increased ucp1 gene expression. PKA also catalyzes the phosphorylation of hormone sensitive lipase (HSL) and perilipin (the protein that covers the intra-cellular lipid droplets) triggering activation of the former and dissociation of the latter from the lipid droplets, thus activating lipolysis of triacylglycerol (TG) stores. Released fatty acids (FA) are channeled to the mitochondria where they enter the P-oxidation pathway and then the citric acid cycle, leading to the formation of reduced electron carriers (FADH2 and NADH) which are then oxidized by the respiratory chain. UCP1 dissipates the proton gradient generated by the respiratory chain, leading to a release of energy as heat (thermogenesis). CM, chylomicrons;

VLDL, very low density lipoproteins; LPL, lipoprotein lipase.

of food, that representing the obligatory cost of nutrient utilization (digestion, absorption, processing and storage): because the body has no storage capacity for protein, protein needs to be metabolically processed immediately, with a high ATP cost associated with protein synthesis and peptide bond formation, urea production and gluconeogenesis from amino acids.

In addition, evidence is accumulating as to the effects of particular food components on the thermogenic system, thus supporting our hypothesis for developing thermogenic foods (i.e. foods enriched in thermogenic active ingredients) to combat obesity (see references 47 and 48). On the one hand, there are a number of food components (e.g. caffeine, catechin polyphenols, ephedrine) known to stimulate the activity of the sympathoadrenergic system or the release of noradrenaline from the adrenals (e.g. capsaicin). On the other hand, certain nutrients/foods - such as vitamin A, carotenoids, olive oil, medium-chain triacylglycerols, polyunsaturated fatty acids (PUFAs) and dietary protein - have been shown to have the potential to stimulate the expression of the UCPs in tissues. For instance, rats adapted to medium and high protein exposure have increased expression levels of UCP2 in liver and UCP1 in BAT, this correlating with a higher energy expenditure and oxygen consumption in the dark period and a lower feed energy efficiency.49 Replacement of habitual foods with others that may enhance energy expenditure may be a practical way to maintain a stable body weight or to help achieve weight loss. The effects of specific foods and food components on the thermogenic system are discussed in more detail in Section 4.5.

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