Cold-induced Brown Adipose Tissue Activation Research Articles

Correction of Nathan Vidal et al. (2023). Assessing the reliability of an infrared thermography protocol to assess cold-induced brown adipose tissue activation in French psychology students

Correction of Nathan Vidal et al. (2023). Assessing the reliability of an infrared thermography protocol to assess cold-induced brown adipose tissue activation in French psychology students

Metabolic Effects of Brown Adipose Tissue Activity Due to Cold Exposure in Humans: A Systematic Review and Meta-Analysis of RCTs and Non-RCTs.

Brown adipose tissue (BAT), specialized in thermoregulation in mammals, has been linked to improved glucose and lipid homeostasis when activated by cold exposure (CE). This systematic review and meta-analysis assessed the metabolic effects of CE-induced BAT activation in healthy humans, examining changes in glucose and lipid metabolism compared to thermoneutrality (TN). A literature search was conducted, identifying relevant human studies, including randomized controlled trials (RCTs) and non-RCTs, based on predefined inclusion criteria. Seven studies (a total of 85 participants) fully met the criteria. Data on plasma glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) were extracted for meta-analysis. When comparing TN and CE under fasting conditions, there were no significant changes in glucose, insulin, or TG concentrations (all p > 0.36). In contrast, CE significantly increased FFA concentrations (p = 0.002; n = 38). Bias was absent for all parameters, but heterogeneity was observed for insulin (I2 = 74.8%). CE primarily affects FFA concentration, likely reflecting cold-induced BAT activity. This suggests that circulating FFAs, serving as the primary fuel for thermogenesis, could indicate BAT activation. However, understanding the effects of BAT activation on overall metabolism requires a broader approach beyond fasting glucose and lipid concentration measurements.

Assessing the reliability of an infrared thermography protocol to assess cold-induced Brown Adipose Tissue activation in french psychology students

The authors use infrared thermography measurements of skin temperature to non-invasively assess the heat production of Brown Adipose Tissue (BAT). In species other than humans, BAT has been linked to maternal care, and may thus be crucial for understanding differences in attachment security. Whereas early BAT research measured its relative presence in the human body through radioactive tracers, researchers have recently used infrared thermography measurement of skin temperature in cold conditions to study BAT thermogenesis outside of medical facilities. Infrared thermography relies on comparing skin temperature in the supraclavicular region (where a BAT depot is located) with skin temperature in the sternal region (which contains no BAT depots) in cold conditions, when the supraclavicular BAT depot produces heat. We replicated an infrared thermography protocol, which previously reported an increase of 0.2 °C in supraclavicular (vs. sternal) skin temperature in cold (vs. control) conditions in only 7 adults, which probably led to overestimation of the effect. With a much larger sample size (N = 94 young adults) and a similar protocol, we did not find any significant variation in relative, Cohen’s d = 0.10, 95% CI [-0.31, 0.50], or absolute supraclavicular skin temperature, Cohen’s d = 0.11, 95% CI [-0.30, 0.52]. Using conditional random forests, we also excluded a variety of alternative explanations for why the method failed to achieve an effect. This protocol of infrared thermography cannot measure BAT thermogenesis and is thus not recommended for future studies to study individual differences in attachment.

Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men

Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24h (95% CI 40-266 kcal/24h) after placebo and 186 kcal/24h (95% CI 94-277 kcal/24h, p=0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36g/ml, 95% CI 2.69-4.02g/ml, vs 3.07g/ml, 95% CI 2.52-3.62g/ml, p=0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

1634-P: Brown Adipose Tissue and Muscle Responses to Tolerable Cold in Black and White Young Lean Men

There has been a renewed interest in brown adipose tissue (BAT) as a therapeutic target for diabetes and obesity treatments due to its ability to consume glucose and expend energy in response to cold temperatures and Beta-adrenergic stimulation. However, comparisons of BAT in different races are limited. To address this knowledge gap, we directly compared healthy, young, lean Black and White men in a controlled inpatient study using a whole-room indirect calorimeter. 12 Black and 12 White men completed a 6-13-day protocol with randomized calorimeter temperatures between 18-31°C for 5 hours. Resting metabolic rate (RMR) was measured under reclined, fasted conditions with standard clothing. Body composition was measured by dual x-ray absorptiometry and BAT and muscle glucose uptake activity was quantified using 18-F Fluorodeoxyglucose (18-F FDG) PET-CT following the last chamber study where each individual's coldest tolerable temperature (Tct) was used. Basal metabolic rate (BMR) was defined as minimum RMR and the cold-induced thermogenesis (CIT) was calculated as the percentage increase of RMR above BMR in the cold. The groups were similar in age (23.8±4.7 yrs) and BMI (23.1±1.5 kg/m2) and their Tct (21.0±1.4°C; p=0.54) and CIT (12.1±8.1 kcal/h; p=0.8) were not different. While White males had significantly higher BAT volume (334 ± 188mL vs 242 ± 89mL; p=0.045), BAT volume was comparable between the groups after normalizing to body volume. BAT activity was similar between the groups. Among all muscle activity measured, the intercostal muscles in the Black males had significantly higher activity (p=0.002) and activity was present in all 12 Black participants but only 4 of 12 White males. Individual BAT or muscle activity did not correlate with each other nor with Tct or CIT. Our data suggest that the cold-induced BAT activity was comparable in Black and White young, lean men. The surprising difference in intercostal muscle activity warrants further investigation. Disclosure R.J.Thomas: None. R.Brychta: None. A.B.Courville: None. S.Mcgehee: None. A.M.Cypess: None. K.Y.Chen: None.

Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice

ObjectiveMaresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. MethodsMaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6−/−) mice. ResultsIn cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6−/− mice. ConclusionsThese data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

Breathe and burn: Novel roles for myoglobin in thermogenesis

Breathe and burn: Novel roles for myoglobin in thermogenesis

Brown-fat-mediated tumour suppression by cold-altered global metabolism

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1–6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1—the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.

PET/MRI-Evaluated Activation of Brown Adipose Tissue via Cold Exposure Impacts Lipid Metabolism.

Although brown adipose tissue (BAT) is considered to play a protective role against obesity and type 2 diabetes, the mechanisms of its activation and associations with clinical parameters are not well described. Male adults underwent a 2 h cold exposure (CE) to activate BAT and, based on the results of PET/MRI performed after the CE, were divided into BAT(+) and BAT(−) groups. During the CE procedure, blood samples were collected and alterations in plasma metabolome in both groups were investigated using LC-MS. Additionally, associations between clinical factors and BAT were examined. Moreover, levels of glucose, insulin, leptin, TNF-α, FGF21, and FABP4 were assessed in serum samples. In the BAT(+) group, levels of LPC(17:0), LPE(20:4), LPE(22:4), LPE(22:6), DHA, linoleic acid, and oleic acid increased during CE, whereas levels of sphinganine-phosphate and sphingosine-1-phosphate decreased. Levels of LPE(O-18:0), 9-HpODE, and oleic acid were elevated, while the level of LPE(20:5) was reduced in BAT(+) compared to BAT(−) subjects. AUCs of LPC(18:2), LPC(O-18:2)/LPC(P-18:1), and SM(d32:2) negatively correlated with BAT. In the BAT(+) group, the concentration of FABP4 during and after CE was decreased compared to the basal level. No alterations were observed in the BAT(−) group. In conclusion, using untargeted metabolomics, we proved that the plasma metabolome is affected by cold-induced BAT activation.

Many Ways to Rome: Exercise, Cold Exposure and Diet-Do They All Affect BAT Activation and WAT Browning in the Same Manner?

The discovery of functional brown adipose tissue (BAT) in adult humans and the possibility to recruit beige cells with high thermogenic potential within white adipose tissue (WAT) depots opened the field for new strategies to combat obesity and its associated comorbidities. Exercise training as well as cold exposure and dietary components are associated with the enhanced accumulation of metabolically-active beige adipocytes and BAT activation. Both activated beige and brown adipocytes increase their metabolic rate by utilizing lipids to generate heat via non-shivering thermogenesis, which is dependent on uncoupling protein 1 (UCP1) in the inner mitochondrial membrane. Non-shivering thermogenesis elevates energy expenditure and promotes a negative energy balance, which may ameliorate metabolic complications of obesity and Type 2 Diabetes Mellitus (T2DM) such as insulin resistance (IR) in skeletal muscle and adipose tissue. Despite the recent advances in pharmacological approaches to reduce obesity and IR by inducing non-shivering thermogenesis in BAT and WAT, the administered pharmacological compounds are often associated with unwanted side effects. Therefore, lifestyle interventions such as exercise, cold exposure, and/or specified dietary regimens present promising anchor points for future disease prevention and treatment of obesity and T2DM. The exact mechanisms where exercise, cold exposure, dietary interventions, and pharmacological treatments converge or rather diverge in their specific impact on BAT activation or WAT browning are difficult to determine. In the past, many reviews have demonstrated the mechanistic principles of exercise- and/or cold-induced BAT activation and WAT browning. In this review, we aim to summarize not only the current state of knowledge on the various mechanistic principles of diverse external stimuli on BAT activation and WAT browning, but also present their translational potential in future clinical applications.

Brown Adipose Tissue Prevalence Is Lower in Obesity but Its Metabolic Activity Is Intact.

Due to its high metabolic activity, brown adipose tissue (BAT) has become a promising target for the development of novel treatment concepts for metabolic disease. Despite several reports of a negative association between the presence of active BAT and obesity, very little is known about the quantitative and qualitative differences of BAT in lean and obese individuals. Systematic studies directly comparing cold-induced BAT activity in leanness and obesity are currently lacking. Here we studied BAT mass and function in 31 lean and 64 obese men and women. After a standardized cooling protocol using a water-perfused vest, 18F-FDG-positron emission tomography/computed tomography scans were performed, and BAT was delineated using lean body-mass adjusted standardized uptake value (SUV) thresholds in anatomic regions with fat radiodensity. Cold-induced thermogenesis (CIT), a functional readout of BAT activity, was quantified by indirect calorimetry. Active BAT was present in a significantly higher proportion of lean than obese individuals (58% vs. 33%, p=0.019). In these participants with active BAT, however, BAT volume and activity did not differ between leanness and obesity. Accordingly, CIT was similar in both weight groups. BAT metrics were not related to adiposity or total fat mass per se. However, in obese participants a strong negative correlation existed between visceral adipose tissue and BAT volume, 18F-FDG uptake and CIT. In summary, despite a significantly lower prevalence of BAT, the metabolic activity and thermogenic capacity of BAT appears to be still intact in obesity and is inversely associated with visceral fat mass.

Brown adipose tissue activation is not related to hypermetabolism in emphysematous chronic obstructive pulmonary disease patients.

BackgroundBrown adipose tissue (BAT) has been primarily researched as a potential target for mitigating obesity. However, the physiological significance of BAT in relation to cachexia remains poorly understood. The objective of this study was to investigate the putative contribution of BAT on different components of energy metabolism in emphysematous chronic obstructive pulmonary disease (COPD) patients.MethodsTwenty COPD patients (mean ± SD age 62 ± 6, 50% female, median [range] BMI 22.4 [15.1–32.5] kg/m2 and 85% low FFMI) were studied. Basal metabolic rate (BMR) was assessed by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water and physical activity by triaxial accelerometry. BMR was adjusted for fat‐free mass (FFM) as assessed by deuterium dilution. Analysis of BAT and WAT was conducted in a subset of ten patients and six age‐matched, gender‐matched and BMI‐matched healthy controls. BAT glucose uptake was assessed by means of cold‐stimulated integrated [18F]FDG positron‐emission tomography and magnetic resonance imaging. WAT was collected from subcutaneous abdominal biopsies to analyse metabolic and inflammatory gene expression levels. Lung function was assessed by spirometry and body plethysmography and systemic inflammation by high sensitivity C‐reactive protein.ResultsMean TDEE was 2209 ± 394 kcal/day, and mean BMR was 1449 ± 214 kcal/day corresponding to 120% of predicted. FFM‐adjusted BMR did not correlate with lung function or C‐reactive protein. Upon cooling, energy expenditure increased, resulting in a non‐shivering thermogenesis of (median [range]) 20.1% [3.3–41.3] in patients and controls. Mean BAT glucose uptake was comparable between COPD and controls (1.5 [0.1–6.2] vs. 1.1 [0.7–3.9]). In addition, no correlation was found between BMR adjusted for FFM and BAT activity or between cold‐induced non‐shivering energy expenditure and BAT activity. Gene expression levels of the brown adipocyte or beige markers were also comparable between the groups. No (serious) adverse events were reported.ConclusionsAlthough COPD patients were hypermetabolic at rest, no correlation was found between BMR or TDEE and BAT activity. Furthermore, both BAT activity and gene expression levels of the brown adipocyte or beige markers were comparable between COPD patients and controls.

Activating thermogenesis to combat obesity: hot topic or cold front?

Activating thermogenesis to combat obesity: hot topic or cold front?

Free Thyroxine Levels are Associated with Cold Induced Thermogenesis in Healthy Euthyroid Individuals.

Thyroid hormone (TH) is an important regulator of mammalian metabolism and facilitates cold induced thermogenesis (CIT) in brown adipose tissue (BAT). Profound hypothyroidism or hyperthyroidism lead to alterations in BAT function and CIT. In euthyroid humans the inter-individual variation of thyroid hormones is relatively large. Therefore, we investigated whether levels of free thyroxine (T4) or free triiodothyronine (T3) are positively associated with CIT in euthyroid individuals. We performed an observational study in 79 healthy, euthyroid volunteers (mean age 25.6 years, mean BMI 23.0 kg · m-2). Resting energy expenditure (REE) was measured by indirect calorimetry during warm conditions (EEwarm) and after a mild cold stimulus of two hours (EEcold). CIT was calculated as the difference between EEcold and EEwarm. BAT activity was assessed by 18F-FDG-PET after a mild cold stimulus in a subset of 26 participants. EEcold and CIT were significantly related to levels of free T4 (R2 = 0.11, p=0.0025 and R2 = 0.13, p=0.0011, respectively) but not to free T3 and TSH. Cold induced BAT activity was also associated with levels of free T4 (R2 = 0.21, p=0.018). CIT was approximately fourfold higher in participants in the highest tertile of free T4 as compared to the lowest tertile. Additionally, free T4 was weakly, albeit significantly associated with outdoor temperature seven days prior to the respective study visit (R2 = 0.06, p=0.037). These finding suggests that variations in thyroid hormone levels within the euthyroid range are related to the capability to adapt to cool temperatures and affect energy balance.

Reduced brown adipose tissue activity during cold exposure is a metabolic feature of the human thrifty phenotype

BackgroundWe recently demonstrated that thrifty subjects, characterized by a greater decrease in 24 h energy expenditure (24hEE) during short-term fasting, have less capacity for cold-induced thermogenesis (CIT) during 24 h of mild cold exposure. ObjectiveAs cold-induced brown adipose tissue activation (CIBA) is a determinant of CIT, we sought to investigate whether thrifty individuals also have reduced CIBA. MethodsTwenty-four healthy subjects (age: 29.8 ± 9.5y, body fat: 27.3 ± 12.4%, 63% male) were admitted to our clinical research unit and underwent two 24hEE assessments in a whole-room indirect calorimeter during energy balance and fasting conditions at thermoneutrality to quantify their degree of thriftiness. Positron emission tomography/computed tomography scans were performed after exposure to 16 °C for 2 h to quantify peak CIBA. ResultsA greater decrease in 24hEE during fasting was associated with lower peak CIBA (r = 0.50, p = 0.01), such that a 100 kcal/day greater reduction in 24hEE related to an average 3.2 g/mL lower peak CIBA. ConclusionOur results indicate that reduced CIBA is a metabolic trait of the thrifty phenotype which might explain reduced CIT capacity and greater predisposition towards weight gain in individuals with a thrifty metabolism.

Brown adipocyte-derived exosomal miR-132-3p suppress hepatic Srebf1 expression and thereby attenuate expression of lipogenic genes

Recent evidence has revealed a novel signaling mechanism through which brown adipose tissue (BAT)-derived exosomal microRNAs (miRNAs) influence hepatic gene expression. Here, we uncover neuronal control of these miRNAs and identify exosomal miR-132-3p as a regulator of hepatic lipogenesis under cold stress conditions. Norepinephrine, a sympathetic nervous system neurotransmitter mediating cold-induced BAT activation, altered the composition of brown adipocyte (BAC)-derived exosomal miRNAs; among them, miR-132-3p was significantly induced. The isolated BAC-derived exosomes suppressed expression of hepatic Srebf1, a predicted target of miR-132-3p. In an indirect co-culture system, BACs suppressed expression of hepatic Srebf1 and its target lipogenic genes; this effect was not seen with miR-132-3p–inhibited BACs. Srebf1 was experimentally validated as an miR-132-3p target. Cold stimuli consistently induced miR-132-3p expression in BAT and attenuated Srebf1 expression in the liver. Our results suggest that BAT-derived exosomal miR-132-3p acts as an endocrine factor that regulates hepatic lipogenesis for cold adaptation.

1709-P: Increased Adiponectin Levels Are Associated with Impaired Brown Adipose Tissue in Mice

Brown adipose tissue (BAT) thermogenesis affects energy expenditure, as well as glucose and lipid clearance. Thus, making BAT an attractive target in obesity/type-2 diabetes. Adiponectin (Apn) regulates whole-body metabolism and lowered Apn levels are associated with obesity and increased type-2 diabetes risk. Apn has been suggested to be required for maintaining normal body temperature in cold environment, but the role of Apn in BAT functionality is not clear. Here, we have studied BAT in adiponectin overexpressing (Apn-Tg) mice. During unchallenged chow-diet conditions, BAT of Apn-Tg mice was enlarged, fibrotic and more whitish. This phenotype was, as judged by tracer experiments, associated with lower lipid and glucose uptake, decreased de novo lipogenesis and decreased fatty acid oxidation in BAT. High-fat diet (HFD)-induced obesity increased these differences between genotypes. The BAT mRNA expression of thermogenesis markers such as UCP-1 and DIO-2 were down-regulated in BAT of obese, but not lean, Apn-Tg mice. Moreover, Seahorse-based analysis revealed reduced mitochondrial function in Apn-Tg BAT in ex vivo-differentiated brown adipocytes. To test whether increased Apn levels affect cold-induced BAT activation, we exposed Apn-tg and littermate control mice to cold temperature (6°C) for four weeks. Under this setting, the BAT lipid and glucose uptake, and body temperature were similar between genotypes. Accordingly, UCP-1 and DIO-2 mRNA levels were not different between Apn-Tg and WT mice, and highly induced by chronic cold exposure. Nevertheless, Seahorse data from isolated BAT mitochondria from cold-exposed animals still indicate mitochondrial dysfunction in Apn-Tg mice. Thus, our data suggest that increased adiponectin levels are associated with metabolic dysfunction in BAT. We propose that the increased BAT expansion in Apn-Tg mice occurs at the expense of the mitochondrial function. Disclosure B. Chanclon: None. M. Bauza-Thorbrugge: None. A. Benrick: None. I. Wernstedt-Asterholm: None.

High Brown Fat Activity Correlates With Cardiovascular Risk Factor Levels Cross-Sectionally and Subclinical Atherosclerosis at 5-Year Follow-Up.

Brown adipose tissue (BAT) activity correlates negatively with obesity and insulin resistance, and BAT has been suggested to act as a protective factor against atherogenesis. We aimed to examine subclinical atherosclerosis and risk factor levels in a group of individuals who had 5 years earlier participated in positron-emission tomography studies with measurements of BAT activity. Approach and Results: Study cohort (males/females=5/26, baseline age 41.4±7.9 years; body mass index, 26.8±6.3 kg/m2) underwent positron-emission tomography imaging at baseline with [18F] FDG (glucose uptake) and [15O] H2O (perfusion) to measure BAT activity during cold exposure. At 5-year follow-up, ultrasound was performed to measure carotid intima-media thickness, carotid distensibility (a marker of arterial elasticity), and brachial flow-mediated dilation (an estimate of endothelial function). Fasting plasma lipids and hemoglobin A1c were measured from venous samples at baseline and at follow-up. Median values were used as cut points for high cold-induced BAT activity (BAT glucose uptake >2.40 μmoL/100 g per minute and perfusion >8.4 mL/100 g per minute). Baseline cold-induced BAT glucose uptake and perfusion correlated directly with carotid distensibility and inversely with mean bulbus intima-media thickness and maximum intima-media thickness (P always ≤0.02). Baseline body mass index, plasma triglycerides, and HbA1c correlated negatively with BAT glucose uptake and perfusion in cold (P always ≤0.048). Correlations between cold-induced BAT activity, cardiovascular risk factors, and atherosclerosis were attenuated with corrections for multiple comparisons. Cold-induced BAT activity at baseline seems to correlate with lower levels of conventional cardiovascular risk factors at baseline and with lower carotid intima-media thickness and higher carotid elasticity at 5-year follow-up.

Fibroblast Growth Factor-21, Leptin, and Adiponectin Responses to Acute Cold-Induced Brown Adipose Tissue Activation.

BackgroundAdipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored.ObjectiveOur study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults.DesignNineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity.Main Outcome MeasuresPlasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA).ResultsPlasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P = 0.03), and inversely correlated with MR sFF (coefficient, −404; P = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects.ConclusionHigher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.HighlightsA higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.