How does thermogenesis occur

Besides Ucp1 induction, TH also regulates mitochondrial protein expression and activity in the cold. Hypothyroid mice have impaired cytochrome c oxidase activity in their BAT upon cold exposure, indicating that cold alone is not sufficient to increase mitochondrial respiration [ 91 ]. On the other hand, the activity of cytochrome c oxidase in the BAT is increased by hyperthyroidism and enhanced further upon cold exposure [ 91 ].

Therefore, TH and cold exposure may have synergistic effects on mitochondrial biogenesis and activity. Since BAT has a high mitochondrial content, it is not only metabolically active, but also prone to oxidative damage. Increases in the level of reduced glutathione, as well as activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase suggest there is an elevated level of reactive oxidative species ROS in rat BAT during cold acclimation [ 95 , 96 ].

This increase in ROS can lead to oxidized protein and mitochondrial damage resulting in decreased mitochondrial function. In response, BAT utilizes autophagy to remove damaged organelles such as mitochondria mitophagy. Mice with an adipose-specific impairment of autophagy have more mitochondria in their adipose tissue [ 97 ] suggesting that autophagy is essential for mitochondrial clearance in the BAT. At present, it is still controversial how autophagy in the BAT is regulated during the adaptive thermogenesis, since both autophagy inhibition and induction have been observed upon cold exposure [ 98 , 99 , ].

Nevertheless, mitophagy in the BAT is important to maintain mitochondrial quality control during thermogenesis [ 22 , 99 ]. T 3 directly stimulates mitophagy in the BAT in order to prevent oxidative damage in the cells.

BAT-specific knockdown of Atg5 to inhibit autophagy blocks the increase in body temperature by T 3 , suggesting that autophagy in the BAT is essential for T 3 -mediated thermogenesis [ 22 ]. In summary, TH regulates coordinated mitochondrial turnover by concomitantly stimulating mitochondrial biogenesis and mitophagy. This coordinated turnover is highly efficient and sufficient to prevent ROS accumulation and protein oxidation in the BAT, since there is no concurrent induction of antioxidant enzymes e.

Currently, there are no reports on the combined effects of TH and cold on autophagy and anti-oxidant enzyme induction in the euthyroid state. It is possible that TH may ameliorate some of the cold-induced oxidative damage by promoting mitophagy, but more research is needed to determine the additive effects of TH and cold.

Prolonged cold exposure induces browning of a subpopulation of white adipocytes interspersed within the subcutaneous WAT [ ]. This browning of white fat increases thermogenic capacity in order to maintain body temperature. Mice rendered hyperthyroid showed an increased expression of BAT markers in their subcutaneous WAT after 3—4 weeks [ 53 , ]. T 3 treatment also directly increased mitochondrial gene expression in human multipotent adipose-derived stem cells [ ] and induced Ucp1 expression in a TR-dependent manner [ ].

However, these findings stand in contrast to other studies that showed TH increased BAT activity [ 22 , 53 , 54 , 55 , 57 ]. It is not clear whether one isoform may play a more important role in central regulation and the other in peripheral regulation of the BAT. More studies need to be performed in order to understand the mechanism s of browning by TH, determine the features that distinguish browning from BAT activation by TH.

Although most of the studies on TH-activated thermogenesis focused on the effects of T 4 and T 3 , the metabolites of TH can also regulate thermogenesis. Administration of T 2 increases sympathetic innervation and vascularization of tissue, and directly increases the BAT oxidative capacity [ ].

On the other hand, another metabolite, 3-iodothyronamine 3-T1AM , has been found to inhibit thermogenesis [ ]. It induces a severe reduction in body temperature when administered to mice, likely due to tail vasodilation and increased heat loss [ ]. Since the effects of TH metabolites on thermogenesis may be different from TH, more studies are needed to better understand the relevance of TH metabolites in regulating thermogenesis.

Although the classical pathway for the adaptive thermogenesis in the BAT has been well studied, the role of TH in thermoregulation is only partially understood. Sympathetic activation appears to be the main driver for thermogenic activation; however, the induction of Dio2 in the BAT and WAT during cold exposure strongly implicates an indispensable role of intracellular T 3 in adipose tissues during thermogenesis.

TH stimulation of the BAT promotes utilization of glucose and fatty acids as fuels, with the latter playing the predominant role during chronic stimulation. TH also promotes autophagy, which facilitates mitochondrial turnover during the activated thermogenesis.

Careful titration of TH and targeted delivery e. Given the current obesity epidemic, stimulation of the BAT function and browning of the WAT by TH suggest that TH or its analogs could be promising therapeutic agents to increase energy expenditure and counteract weight gain.

Conceptualization, P. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Int J Mol Sci. Published online Apr Winifred W.

Yau 1 and Paul M. Paul M. Author information Article notes Copyright and License information Disclaimer. Received Mar 23; Accepted Apr This article has been cited by other articles in PMC. Abstract Thermogenesis is the production of heat that occurs in all warm-blooded animals. Keywords: thermogenesis, thyroid hormone, brown adipose tissue, browning. Introduction 1. Thermogenesis and Adipose Tissue Thermogenesis is an essential survival mechanism for homeotherms. Open in a separate window.

Figure 1. TH Increases Lipogenesis Maintaining a healthy pool of intracellular lipids is important in order to support a high metabolic rate in the BAT.

TH Increases Mitophagy Since BAT has a high mitochondrial content, it is not only metabolically active, but also prone to oxidative damage. Summary Although the classical pathway for the adaptive thermogenesis in the BAT has been well studied, the role of TH in thermoregulation is only partially understood. Author Contributions Conceptualization, P. Conflicts of Interest The authors declare no conflict of interest.

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Here, the focus is on DIT as a function of the energy content and nutrient composition of the test food consumed and the duration of the postprandial measurement period in adult subjects with a normal bodyweight. The review is based on literature published over the last 15 years. The experimental design of most studies on DIT is a measurement of resting energy expenditure before and after a test meal, with a ventilated hood system. The observation is started after an overnight fast, where subjects are refrained from eating after the last meal at Thus, with observations starting between Postprandial measurements are made for several hours where subjects have to remain stationery, most often in a supine position, for the duration of the measurements.

In some studies, measurements are 30 min with 15 min intervals allowing i. The use of a respiration chamber to measure DIT has the advantage of reproducing more physiological conditions over a longer period of time while regular meals are consumed throughout the day [ 5 , 6 ]. The DIT, as observed in a respiration chamber over 24 h has been evaluated in different ways: 1 as the difference in h energy expenditure between a day in the fed state and a day in the fasted state; 2 as the difference in daytime energy expenditure adjusted for the variability of spontaneous activity and basal metabolic rate; and 3 as the difference in h energy expenditure adjusted for the variability of spontaneous activity and basal metabolic rate.

Studies on DIT were selected from Medline. Studies were selected when information was presented on energy intake, diet composition with respect to carbohydrate, protein fat and alcohol of the test food, duration of the postprandial measurement, and DIT. The figures for the respiration chamber measurements are for the h DIT calculation as described above under method 3. The mean pattern of DIT throughout the day is presented in figure 1.

Data are from a study where DIT was calculated by plotting the residual of the individual relationship between energy expenditure and physical activity in time, as measured over min intervals from a h observation in a respiration chamber [ 10 ].

Subjects were 17 females and 20 males. The level of resting metabolic rate after waking up in the morning, and directly before the first meal, was defined as basal metabolic rate. Resting metabolic rate did not return to basal metabolic rate before lunch at 4 h after breakfast, or before dinner at 5 h after lunch. Overnight, basal metabolic rate was reached at 8 h after dinner consumption. The mean pattern of diet induced thermogenesis throughout the day, calculated by plotting the residual of the individual relationship between energy expenditure and physical activity in time, as measured over min intervals from a h observation in a respiration chamber.

Subjects were 17 females and 20 males [10]: , level of basal metabolic rate; arrows, meal times. Fifteen studies on DIT with information on energy intake, on diet composition and on the postprandial measurement period were selected from literature Table 1.

Five studies compared DIT, as measured with the same protocol in the same subjects, for two or more diets with a different composition. For alcohol, there was a tendency for an increased DIT, from 7. In a second study, with a similar energy exchange with alcohol, there was a significant increase in DIT, from 7.

For protein, there was a tendency for and increased DIT, from 7. In a second study, with a similar energy exchange with protein, there was a significant increase in DIT, from Only three of the 22 studies presented in table 1 included alcohol as a nutrient and were excluded.

In a regression analysis of the remaining 19 studies, the protein fraction of the food came out as significant determinant of DIT. The main determinant of DIT is the energy content of the food, followed by the protein fraction of the food. The thermic effect of alcohol is similar to the thermic effect of protein.

Diet induced thermogenesis is related to the stimulation of energy-requiring processes during the post-prandial period. The intestinal absorption of nutrients, the initial steps of their metabolism and the storage of the absorbed but not immediately oxidized nutrients [ 15 ]. As such, the amount of food ingested quantified as the energy content of the food is a determinant of DIT. The most common way to express DIT is derived from this phenomenon, the difference between energy expenditure after food consumption and basal energy expenditure, divided by the rate of nutrient energy administration [ 16 ].

Theoretically, based on the amount of ATP required for the initial steps of metabolism and storage, the DIT is different for each nutrient. The studies with a higher value included a study with pure alcohol consumption and the studies where DIT was measured over 24 h in a respiration chamber.

In the respiration chamber studies, DIT values were calculated as the increase in energy expenditure above sleeping metabolic rate while the other studies reported DIT as the increase in energy expenditure above basal metabolic rate. The higher DIT value of alcohol and protein compared with carbohydrate and fat has implications for the effect of these nutrients on energy balance.

However, the main effect on energy balance does not seem to be primarily linked to the lower bioavailability of alcohol-and protein energy than that of fat and carbohydrate.

Alcohol energy is largely additive to the normal diet but does not seem to affect energy balance positively [ 18 ]. Protein plays a key role in food intake regulation through satiety related to DIT [ 19 ]. Alcohol forms a significant component of many diets and it supplements rather than displaces daily energy intake.

Alcohol consumption as an aperitif has even been shown to result in a higher subsequent intake with no intake compensation afterwards [ 20 ]. Yet, alcohol intake does not systematically increase body weight. In a recent study, it was shown that subjects with higher alcohol consumption are habitually more active [ 21 ].

This may be one explanation for the lack of increasing body weight through additional energy intake from alcohol. The main effect of protein on energy balance is thought to be DIT related satiety.

The observed DIT related satiety might be ascribed to the high protein rather than the high carbohydrate content of the diet. The DIT increases body temperature, which may be translated into satiety feelings. High-protein diets are favored for weight maintenance, also after weight loss, by favoring maintenance or regain of fat-free mass, by reducing the energy efficiency through a higher thermogenesis, and by reducing intake through an increased satiety [ 19 ].

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