Thermogenesis In Obesity Research Articles

Triiodothyronine (T3) promotes browning of white adipose through inhibition of the PI3K/AKT signalling pathway

Obesity arises from an imbalance between energy consumption and energy expenditure, and thyroid hormone levels serve as a determinant of energy expenditure. We conducted experiments at the animal and cellular levels and combined those findings with clinical data to elucidate the role of triiodothyronine (T3) in facilitating the browning of white adipose tissue (WAT) and its underlying mechanism. The results showed (i) the impaired metabolic function of local WAT and the compensatory elevation of systemic thermogenesis in obesity; (ii) T3 treatment of white adipocytes in vitro and local WAT in vivo induced a shift towards a morphologically “brown” phenotype, accompanied by upregulation of mRNA and protein expression of browning-related and mitochondrial function markers, which suggest that T3 intervention promotes the browning of WAT; and (iii) the aforementioned processes could be modulated through inhibition of the PI3K/AKT signalling pathway; however, whether T3 affects the PI3K/AKT signalling pathway by affecting insulin signalling remains to be studied and clarified. The results of our study indicate that T3 treatment promotes browning of WAT through inhibition of the PI3K/AKT signalling pathway; these findings offer novel perspectives regarding the potential of localised therapies for addressing WAT volume in individuals with obesity.

Rhein targets macrophage SIRT2 to promote adipose tissue thermogenesis in obesity in mice

Rhein, a component derived from rhubarb, has been proven to possess anti-inflammatory properties. Here, we show that rhein mitigates obesity by promoting adipose tissue thermogenesis in diet-induced obese mice. We construct a macrophage-adipocyte co-culture system and demonstrate that rhein promotes adipocyte thermogenesis through inhibiting NLRP3 inflammasome activation in macrophages. Moreover, clues from acetylome analysis identify SIRT2 as a potential drug target of rhein. We further verify that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of SIRT2 abrogates adipose tissue thermogenesis and metabolic benefits in obese mice induced by rhein. Together, our findings elucidate that rhein inhibits NLRP3 inflammasome activation in macrophages by regulating SIRT2, and thus promotes white adipose tissue thermogenesis during obesity. These findings uncover the molecular mechanism underlying the anti-inflammatory and anti-obesity effects of rhein, and suggest that rhein may become a potential drug for treating obesity.

309-OR: Lipocalin 2 Deficiency Impairs Mitochondrial Dynamics and Phospholipid Metabolism in Brown Adipocytes

Impaired mitochondrial bioenergetics in brown adipocytes links to the disrupted energy metabolism and thermogenesis in obesity. Phospholipids, particularly cardiolipin and phosphatidic acid (PA) are critical regulators of mitochondrial membrane architecture and dynamics. Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as the platform for phospholipid biosynthesis. MAM dysfunction disturbs phospholipid metabolism, thereby disrupting mitochondrial function. However, little is known about the participating factors that regulate MAM phospholipid metabolism. We have previously characterized the role of lipocalin 2 (Lcn2) in thermogenesis and mitochondrial function in adipocytes. Herein, we found that Lcn2 was located at MAMs and had a specific PA binding capability. The mitochondrial fusion-fission process induced by the fasting-refeeding cycle was impaired in Lcn2 knockout (KO) brown adipocytes. We also observed that the levels of phosphorylated Drp1 (Ser616) and Opa1 were decreased in brown adipose tissue (BAT) of Lcn2 KO mice compared to WT controls upon acute cold stimulation, whereas Lcn2 overexpression in BAT led to an increase in Drp1 phosphorylation and Opa1 level. Moreover, Lcn2 deficiency significantly enhanced the cold-stimulated accumulation of Opa1 as well as MAM markers SigmaR1, Ip3R1, and Facl4 at MAMs in BAT, suggesting impaired MAM function. CL316,243, a β3-adrenergic receptor agonist has a cold mimic effect on mitochondrial bioenergetics. In brown adipocytes, Lcn2 deficiency significantly attenuated the CL316,243 induction of Drp1 phosphorylation. Intriguingly, lipidomic analysis of BAT mitochondria isolated from mice treated with CL316,243 for 14 days showed that Lcn2 deficiency blunted CL316,243-induced cardiolipin biosynthesis and altered phospholipid metabolism. Together, we discovered a role of Lcn2 as a novel PA transfer protein in mitochondrial bioenergetics via regulating phospholipid metabolism. Disclosure H.Su: None. H.Guo: None. X.Qiu: None. T.Lin: None. X.Chen: None. Funding This work was supported by NIDDK Grant (RDK123042) awarded to Xiaoli Chen.

Differentiating SGBS adipocytes respond to PPAR\u03b3 stimulation, irisin and BMP7 by functional browning and beige characteristics

Brown and beige adipocytes are enriched in mitochondria with uncoupling protein-1 (UCP1) to generate heat instead of ATP contributing to healthy energy balance. There are few human cellular models to reveal regulatory networks in adipocyte browning and key targets for enhancing thermogenesis in obesity. The Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte line has been a useful tool to study human adipocyte biology. Here we report that SGBS cells, which are comparable to subcutaneous adipose-derived stem cells, carry an FTO risk allele. Upon sustained PPARγ stimulation or irisin (a myokine released in response to exercise) treatment, SGBS cells differentiated into beige adipocytes exhibiting multilocular lipid droplets, high UCP1 content with induction of typical browning genes (Cidea, Elovl3) and the beige marker Tbx1. The autocrine mediator BMP7 led to moderate browning with the upregulation of the classical brown marker Zic1 instead of Tbx1. Thermogenesis potential resulted from PPARγ stimulation, irisin and BMP7 can be activated in UCP1-dependent and the beige specific, creatine phosphate cycle mediated way. The beige phenotype, maintained under long-term (28 days) conditions, was partially reversed by withdrawal of PPARγ ligand. Thus, SGBS cells can serve as a cellular model for both white and sustainable beige adipocyte differentiation and function.

Inflammation Attenuates Adaptive Thermogenesis via Autophagy and ER Stress‐Associated Mechanism

Adaptive thermogenesis and browning of white adipose tissue (WAT) is the cellular process to generate heat in response to environmental stimuli including cold temperature. Decrease of adaptive thermogenesis is a contributing factor to exacerbate obesity. The aim of this study is to determine the molecular mechanisms by which obesity compromises adaptive thermogenesis. We hypothesized that a low‐grade chronic inflammation in obesity inhibits WAT browning. C57BL/6 mice were exposed to cold temperature for 2 weeks with injection of either saline or low‐dose LPS to mimic chronic low‐level inflammation. LPS injection significantly decreased thermogenesis than saline as evidenced by lower core body temperature and reduced heat release captured in thermal imaging. LPS‐mediated inflammation markedly decreased WAT browning in subcutaneous fat by dampening down UCP1 and PGC1a expressions, mitochondria‐specific protein levels, and mitochondrial DNA contents suggesting mitochondrial dysfunction. LPS‐mediated inflammation was also associated with an elevated levels of ER stress markers (GRP78, p‐eIF2a, and CHOP) as well as concurrent autophagic activation (increase in beclin‐1, Atg5/Atg12, LC3II). Taken together, our data suggest an existence of novel signaling axis linking adipose inflammation, ER stress, and autophagic activation, which may be responsible for mitochondrial dysfunction and compromised adaptive thermogenesis in obesity.

Lean body mass and food-induced thermogenesis in obesity.

Lean Body Mass and Food-Induced Thermogenesis in Obesity Get access Nutrition Reviews, Volume 45, Issue 11, November 1987, Pages 264–265, https://doi.org/10.1111/j.1753-4887.1987.tb02697.x Published: 01 November 1987

Effect of naltrexone treatment on insulin secretion, insulin action and postprandial thermogenesis in obesity.

For many years a series of studies has been carried out to evaluate the role of endogenous opioid peptides on glucose metabolism. In this work we studied the influence of endogenous opioid peptides on insulin response to OGTT and glucose-induced thermogenesis before and after a prolonged oral treatment with Naltrexone (50 mg/daily for 6 days), an opioid receptor antagonist, in a group of 9 obese subjects. Moreover in obese patients we evaluated the effect of this anti-opioid drug on insulin secretion and insulin sensitivity during an IVGTT using the minimal model approach. We compared the pre-treatment results with data coming from a group of 5 normal-weight subjects. We measured blood glucose, plasma insulin and C-peptide concentrations and evaluated the following parameters: first (phi 1) and second (phi 2) phase of beta-cell sensitivity, insulin sensitivity and glucose effectiveness. Obese subjects displayed an increased insulin response to oral and i.v. glucose load, due to an increased first phase of insulin secretion (phi 1), a reduced insulin sensitivity (Si) and glucose effectiveness (Sg) in respect to normal-weight subjects. They showed no difference in glucose and insulin area during oral load and in their profiles during i.v. glucose load after naltrexone treatment. Similarly no significant variation in insulin sensitivity and glucose effectiveness was observed. The glucose-induced thermogenesis, measured by indirect calorimetry, was not modified by naltrexone. Therefore our study demonstrates that endogenous opioids do not play any role in the impairment of peripheral insulin sensitivity and energy expenditure in human obesity.

Reliability of the measurement of postprandial thermogenesis in men of three levels of body fatness

To determine the reliability of the measurement of postprandial thermogenesis by indirect calorimetry and to clarify further the relationship of obesity to thermogenesis in men, the thermic effect of a 720-kcal, mixed liquid meal was compared in 13 lean men (mean ± SEM, 11.2% ± 1.4% body fat), 10 average men (22.4% ± 1.6% body fat), and 12 obese men (33.4% ± 1.6% body fat) on two occasions. Resting metabolic rate (RMR) was measured for 3 hours: (1) in the fasted state, and (2) after a 720-kcal mixed liquid meal, on two occasions. The thermic effect of the meal, calculated as the postprandial energy expenditure minus the fasting RMR (kcal/3 h), was greater for the lean and average men than for the obese men during both trials ( P < .001), but was only marginally different between the lean and average groups ( P = .16). The mean values for the two trials were similar and the measurement of thermogenesis was highly reproducible with a reliability coefficient of r = .932 ( P < .001). Across all groups, thermogenesis correlated strongly with percent body fat ( r = −.64, P < .01), but within the average men, thermogenesis was uncorrelated with percent body fat ( r = .09) but highly correlated with the glucose response to the meal ( r = −.75, P < .05). Thus, factors other than body fatness, such as insulin sensitivity, may determine thermogenesis within this heterogeneous middle group. These results indicate that postprandial thermogenesis is reliable, confirm the putative defective thermogenesis in obesity, and indicate the importance of careful body composition measurement and classification in the study of thermogenesis and obesity. Furthermore, in men with more than approximately 28% body fat, thermogenesis is consistently blunted.

Independent effects of obesity and insulin resistance on postprandial thermogenesis in men.

The putative blunted thermogenesis in obesity may be related to insulin resistance, but insulin sensitivity and obesity are potentially confounding factors. To determine the independent effects of obesity and insulin resistance on the thermic effect of food, at rest and after exercise, lean and obese men were matched at two levels of insulin sensitivity determined by insulin-stimulated glucose disposal (milligrams per kilogram fat-free mass [FFM] per minute) during the euglycemic, hyperinsulinemic (40 mU/m2.min) clamp: 5.4 mg/kg FFM for the lean and obese groups with low insulin sensitivity, and 8.1 mg/kg FFM for the groups with high insulin sensitivity. The two lean groups were matched for percent fat (approximately 15 +/- 1% fat), as were the two obese groups (approximately 33 +/- 2% fat). Energy expenditure was measured for 3 h in the fasting state and for 3 h after a 720-kcal mixed meal, each at rest and immediately after 1 h of cycling at 100 W. The thermic effect of food (TEF) was calculated as the postprandial minus fasting energy expenditure (kcal/3 h) during rest and after exercise. During rest, TEF was blunted by both obesity (24 +/- 5 and 34 +/- 6 kcal/3 h for obese groups with low and high insulin sensitivity vs. 56 +/- 6 and 74 +/- 6 kcal/3 h for the lean groups with low and high insulin sensitivity; P less than 0.01 lean vs. obese) and insulin resistance (insulin-resistant less than insulin-sensitive, at both levels of obesity; P less than 0.01). After exercise, TEF was also impaired in the obese (47 +/- 6 and 44 +/- 5 kcal/3 h for the insulin-resistant and -sensitive groups) and in the lean insulin-resistant (55 +/- 5 kcal/3 h), compared with the lean insulin-sensitive men (71 +/- 3 kcal/3 h), P less than 0.01. Compared with rest, TEF after exercise was improved, but not normalized, in both obese groups (P less than 0.05), but unchanged in the lean groups. These results suggest that both insulin resistance and obesity are independently associated with impaired TEF at rest, but the responsiveness of thermogenesis to exercise before a meal is related to the obese state and not independently to insulin resistance per se.

Thermic effect of a meal over 3 and 6 hours in lean and obese men

Controversy regarding defective postprandial thermogenesis in obesity may partly be due to methodological factors such as duration of measurement. To clarify further the role of blunted thermogenesis in obesity, the thermic effect of food was compared in seven lean (mean ± SEM, 15.7% ± 1.5% body fat, by densitometry) and seven obese men (37.3% ± 3% fat) over 3 and 6 hours. The groups were matched for age (35 ± 2 and 33 ± 2 years for the lean and obese groups; range, 25 to 39 years), fat-free mass (FFM), and aerobic fitness. Resting metabolic rate (RMR) was measured by indirect calorimetry for 6 hours on two mornings, in randomized order: (1) after a 720-kcal liquid mixed meal, which was 24% protein, 21% fat, and 55% carbohydrate; and (2) in the postabsorptive state. The thermic effect of food, calculated as postprandial minus postabsorptive RMR, was significantly greater for the lean than obese men for the first 3 hours of measurement ( 67 ± 6 v 49 ± 3 kcal 3 hours ; P < .01 ). During the second 3 hours, the thermic effect of food was marginally, but not significantly, greater for the lean than obese men ( 34 ± 8 v 20 ± 4 kcal 3 hours ; P = .10 , NS). Over the entire 6 hours, the thermic effect of food was significantly greater for the lean than obese men ( 100 ± 12 v 69 ± 5 kcal 6 hours ; P < .05 ). Three hours after the meal the increment above fasting RMR was greater for the lean than obese men (28% ± 7% v 13% ± 3% above fasting; P < .05). However, 6 hours after the meal the elevation above fasting RMR was not significantly different between the lean (6% ± 3%) and obese men (0% ± 2%). These results indicate that the thermic effect of food is neither delayed nor more prolonged in obese compared with lean men and provide further evidence for defective thermogenesis in obesity.

Comparison of thermic effects of constant and relative caloric loads in lean and obese men

Controversy regarding defective thermic effect of food (TEF) in obesity might be related to differences among studies in the caloric loads. To clarify further the role of blunted thermogenesis in obesity, responses to the same absolute caloric load (720 kcal) and a relative load, which was 35% of each subject's resting metabolic rate (RMR), were compared in 11 lean (L) and 11 obese (O) men. The relative load was slightly larger for O than L (752 +/- 27 vs 683 +/- 21 kcal; means +/- SEM, NS). TEF, calculated as 3-h postprandial minus fasting RMR, was greater for L than O for both the 720-kcal (69 +/- 4 vs 31 +/- 3 kcal/3 h, p less than 0.01) and relative loads (64 +/- 4 vs 37 +/- 3 kcal/3 h, p less than 0.01). For L, TEF was greater for the 720-kcal load than for the relative load whereas for O, TEF was greater for the relative than for the 720-kcal meal. However, expressed as a percent of the calories ingested, TEF for the absolute and relative meals was identical for each group, in both cases lower for O (4.2 +/- 0.4% vs. 4.7 +/- 0.3%) than for L (9.7 +/- 0.4% vs 9.3 +/- 0.8%); p less than 0.01. These results demonstrate the impact on thermogenesis of the basis on which the meal is dosed and provide further evidence for defective thermogenesis in obesity.

Dietary-induced thermogenesis in obesity. Response to mixed and carbohydrate meals.

The possibility that dietary-induced thermogenesis may be decreased in obesity has been proposed in recent years. However, the results of human studies so far obtained are conflicting. The present research was undertaken in order to clarify this question. We studied postprandial thermogenesis induced by ingestion of a mixed meal and of a carbohydrate mixture in 15 normal and 12 obese subjects. Blood glucose and plasma insulin levels were measured at the same time. The data obtained have shown that the mean resting metabolic rate (RMR) expressed as a function of body weight3/4, is almost the same in obese as in normal-weight subjects (0.115 +/- 0.018 vs 0.133 +/- 0.021 kj/min/kg3/4, respectively). Moreover, the increment of mixed-meal induced thermogenesis (MM-IT) was 48 +/- 22% in normal and -0.8 +/- 12% in obese subjects, respectively (p less than 0.01). Carbohydrate induced thermogenesis (CHO-IT) appeared slightly higher in normal-weight than in obese subjects (159 +/- 66 vs 98 +/- 46). After carbohydrate ingestion we observed a higher glycemic and insulinemic response in obesity. These results indicate that thermogenesis induced by ingestion of food is reduced in obese subjects; they are also compatible with the idea that insulin resistance could play a role in this phenomenon.

Leucocyte sodium pump activity after meals or insulin in normal and obese subjects: cause for increased energetic efficiency in obesity?

As cellular sodium pumping is an energy consuming process and differences in the obese may account for their energetic efficiency, leucocyte sodium-22 efflux was studied in obese and normal volunteers both in the fasting state and after a test meal or infusion of glucose and insulin intravenously. The 22Na ouabain sensitive efflux rate constant was significantly higher in obese subjects than normal (mean (1 SD) 2.69 (0.40)/h v 2.35 (0.49)/h). Two hours after a 4.2 MJ (1000 kcal) meal there was an increase in the efflux rate constant from its fasting value in normal weight subjects (2.39 (0.33)/h to 2.71 (0.40)/h) but not in obese subjects (2.65 (0.54)/h to 2.61 (0.58)/h). The rise in ouabain sensitive efflux rates was significantly higher in normal than obese subjects. Both groups showed a rise in intracellular sodium concentrations. The euglycaemic clamp produced similar results. Feeding or infusion of insulin increases sodium pump activity more in normal than obese subjects. This difference may contribute to any defective dietary thermogenesis in obesity, which may lead to energetic efficiency and a tendency to gain weight.

THE EFFECT OF ORAL GLUCOSE ON THE LEUCOCYTE SODIUM PUMP IN NORMAL AND OBESE SUBJECTS

The effect of oral glucose (40 g/m2 body surface area) on the leucocyte 22Na efflux rate constants (ERC) was studied in 13 normal weight and 10 obese subjects. The ouabain-sensitive 22Na ERC was higher in leucocytes isolated from fasting obese subjects (median [range] for obese 2.77 [2.33-3.11] vs normals 1.91 [1.57-2.77] h-1, P less than 0.001). There was no difference in the ouabain-resistant 22Na ERC. Oral glucose raised the ouabain-sensitive 22Na ERC after 2 h in normal subjects (1.91 [1.57-2.77] to 2.41 [2.11-3.02] h-1, P less than 0.001). The ouabain-resistant 22Na ERC fell from 0.71 [0.32-1.10] to 0.46 [0.35-0.68] h-1, P less than 0.008. Conversely, in obese subjects, the ouabain-sensitive ERC fell (2.77 [2.33-3.11] to 2.59 [2.11-2.92] h-1, P less than 0.06). There was no significant change in ouabain-resistant 22Na ERC 2 h after oral glucose. The fasting leucocyte 22Na ouabain-sensitive ERC correlated with fasting plasma insulin levels and insulin resistance (rs = 0.48, P less than 0.01 for both). The change in this ERC with oral glucose correlated with the incremental insulin response over 2 h (rs = -0.53, P less than 0.006) and to the insulin resistance (rs = -0.56, P less than 0.003). The failure of oral glucose to stimulate the leucocyte sodium pump in obesity could partially account for the defect in dietary thermogenesis in obesity. This defect in stimulation of the sodium pump is related to insulin resistance.

Vasoactive intestinal polypeptide and diet-induced thermogenesis in obesity

Vasoactive intestinal polypeptide and diet-induced thermogenesis in obesity

Erythrocyte sodium-potassium-stimulated adenosine triphosphatase activity is not related to obesity

Altered erthrocyte sodium potassium (Na,K)-stimulated adenosine triphosphatase (ATPase) activity has been cited as having pathophysiologic significance in morbidly obese man. Previous studies have failed to consider obese patients after weight loss and, therefore, did not clarify the role of ATPase deficiency as a cause or effect of the obese state. To define more completely the possible alteration of cellular thermogenesis in obesity, a study was made of three groups of people: (1) normal weight controls; (2) morbidly obese; and (3) formerly morbidly obese patients who had lost over 100 pounds after gastric bypass surgery. Erythrocyte ATPase activity was determined by use of an assay that coupled ATPase activity with NADH oxidation in the presence of excess pyruvate kinase, lactic dehydrogenase, and phosphoenolpyruvate. This coupled assay produced a continuous slope so that activity could be calculated from the initial, maximal, linear portion of the decay trace. Results did not demonstrate any statistically significant differences in Na,K-ATPase activity between groups by analysis of variance. A nonsignificant correlation of 0.086 was seen between obesity index and Na,K-ATPase activity. It is concluded that (1) erythrocyte Na, K-ATPase activity is similar in both normal and obese individuals, (2) erythrocyte Na,K-ATPase does not change with weight loss, and (3) therefore, disordered erythrocyte thermogenesis does not have a role in the development or maintenance of obesity.

Dietary Fat Induced Thermogenesis in Obesity

Dietary Fat Induced Thermogenesis in Obesity

Caffeine: its effect on catecholamines and metabolism in lean and obese humans.

1. The metabolic response of lean and obese women to caffeine was studied to see if caffeine could be used to demonstrate the subnormal thermogenesis in obesity previously shown after standard meals or intravenous infusions of noradrenaline. 2. The rise in resting metabolic rate with caffeine was similar in the lean and obese groups and beta-adrenoceptor blockade did not reduce the increment in metabolic rate in either group. These responses did not, therefore, correspond with the other subnormal thermogenic responses of the constitutionally obese. 3. In a post-obese group, i.e. previously obese women who were now of normal weight, there was a reduced response of the resting metabolic rate to caffeine. 4. Monitoring plasma substrate concentrations showed that the change in oxygen uptake corresponded to changes in plasma free fatty acids, so that in adults the metabolic effects of caffeine seem to be mediated by increases in adipocyte lipolysis. This effect seems to be mainly independent of the adrenergic system.

Reduced thermogenesis in obesity

IT is often claimed that there are obese patients who find it difficult to maintain a normal body weight because they have such low energy requirements that even normal intakes of energy result in weight gain and obesity. Studies of both children1 and adults2 show that there can be a twofold difference in energy intake between individuals despite apparently similar patterns of physical activity. An individual variability in the capacity to dissipate heat by metabolic changes has therefore been suggested3 but no physiological basis for the differences in thermogenesis has yet been established. In genetically obese ob/ob mouse there are two components involved in the deposition of excess body fat: hyperphagia and increased metabolic efficiency4,5. Metabolic efficiency is the major factor responsible for obesity when the animals are kept at 20 °C so these animals provide a model study of the link between metabolic rate and obesity. Pre-obese and obese ob/ob animals have an abnormality of thermoregulatory thermogenesis with a reduced thermogenic response to cooling6. A defect in non-shivering thermogenesis can be confirmed by monitoring the thermogenic response to maximum doses of nor adrenaline: the ob/ob mouse has only half the response of its lean littermate. The abnormal thermoregulatory thermogenesis quantitatively accounts for most of the metabolic efficiency of the obese animals as pair feeding at thermoneutrality rather than at 23 °C reduces the excess fat deposited by 65%7. We report here that obese adults with a family history of obesity have a reduced metabolic response to noradrenaline infusion compared with thin adults. As the reduced non-shivering thermogenesis is also found in subjects with familial obesity who remain at normal weight by persistent dieting, the defect in non-shivering thermogenesis appears to be constitutional and not a secondary consequence of obesity.