Cold-induced Thermogenesis Research Articles

High daily energy expenditure of Tuvan nomadic pastoralists living in an extreme cold environment

Research investigating thermoregulatory energy costs in free-living humans is limited. We determined the total energy expenditure (TEE) of Tuvan pastoralists living in an extreme cold environment and explored the contribution of physical activity and cold-induced thermogenesis. Twelve semi-nomadic pastoralists (47 ± 8 years, 64 ± 8 kg) living under traditional circumstances, in Tuva, south-central Siberia, Russia, were observed during two consecutive 6-day periods in winter. TEE was measured via the doubly labelled water technique. Skin and ambient temperatures, and physical activity were continuously monitored. The outdoor temperature during the observation period was − 27.4 ± 5.4 °C. During the daytime, the participants were exposed to ambient temperatures below 0 °C for 297 ± 131 min/day. The Tuvan pastoralists were more physically active compared to western populations (609 ± 90 min/day of light, moderate, and vigorous physical activity). In addition, TEE was 13.49 ± 1.33 MJ/day (3224 ± 318 kcal/day), which was significantly larger by 17% and 31% than predicted by body mass, and fat-free mass, respectively. Our research suggests the daily cold exposure combined with high levels of physical activity contributed to the elevated TEE. Future research should reconsider the assumption that energy costs due to thermoregulation are negligible in free-living humans.

Tracking footprints of artificial and natural selection signatures in breeding and non-breeding cats

Stray non-breeding cats (stray) represent the largest heterogeneous cat population subject to natural selection, while populations of the Siamese (SIAM) and Oriental Shorthair (OSH) breeds developed through intensive artificial selection for aesthetic traits. Runs of homozygosity (ROH) and demographic measures are useful tools to discover chromosomal regions of recent selection and to characterize genetic diversity in domestic cat populations. To achieve this, we genotyped 150 stray and 26 household non-breeding cats (household) on the Illumina feline 63 K SNP BeadChip and compared them to SIAM and OSH. The 50% decay value of squared correlation coefficients (r2) in stray (0.23), household (0.25), OSH (0.24) and SIAM (0.25) corresponded to a mean marker distance of 1.12 Kb, 4.55 Kb, 62.50 Kb and 175.07 Kb, respectively. The effective population size (Ne) decreased in the current generation to 55 in stray, 11 in household, 9 in OSH and 7 in SIAM. In the recent generation, the increase in inbreeding per generation (ΔF) reached its maximum values of 0.0090, 0.0443, 0.0561 and 0.0710 in stray, household, OSH and SIAM, respectively. The genomic inbreeding coefficient (FROH) based on ROH was calculated for three length categories. The FROH was between 0.014 (FROH60) and 0.020 (FROH5) for stray, between 0.018 (FROH60) and 0.024 (FROH5) for household, between 0.048 (FROH60) and 0.069 (FROH5) for OSH and between 0.053 (FROH60) and 0.073 (FROH5) for SIAM. We identified nine unique selective regions for stray through genome-wide analyses for regions with reduced heterozygosity based on FST statistics. Genes in these regions have previously been associated with reproduction (BUB1B), motor/neurological behavior (GPHN, GABRB3), cold-induced thermogenesis (DIO2, TSHR), immune system development (TSHR), viral carcinogenesis (GTF2A1), host immune response against bacteria, viruses, chemoattractant and cancer cells (PLCB2, BAHD1, TIGAR), and lifespan and aging (BUB1B, FGF23). In addition, we identified twelve unique selective regions for OSH containing candidate genes for a wide range of coat colors and patterns (ADAMTS20, KITLG, TYR, TYRO3—a MITF regulator, GPNMB, FGF7, RAB38) as well as congenital heart defects (PDE4D, PKP2) and gastrointestinal disorders (NLGN1, ALDH1B1). Genes in stray that represent unique selective events indicate, at least in part, natural selection for environmental adaptation and resistance to infectious disease, and should be the subject of future research. Stray cats represent an important genetic resource and have the potential to become a research model for disease resistance and longevity, which is why we recommend preserving semen before neutering.

High-fat diet during pregnancy lowers fetal weight and has a long-lasting adverse effect on brown adipose tissue in the offspring.

Maternal obesity and malnutrition during gestation and lactation have been recognized to increase the risk of obesity and metabolic disorders in the offspring across their lifespan. However, the gestational period during which malnutrition exerts a decisive effect is unclear. Brown adipose tissue (BAT) plays a critical role in energy metabolism owing to its high efficiency in oxidizing glucose and fatty acids. This study aimed to determine the impact of maternal high-fat diet (HFD) consumption only during pregnancy on BAT and energy metabolism in offspring mice. Dams were fed an HFD or a normal chow diet from embryonic day 2.5. HFD consumption during pregnancy induced glucose intolerance and hypertension in dams. In the offspring of HFD-fed dams, maternal HFD lowered fetal weight without affecting placental weight, whereas HFD consumption after birth exacerbated oxygen consumption and cold-induced thermogenesis at 12 months of age, accompanied by increased lipid droplet size in BAT. These data demonstrate that HFD consumption only during pregnancy exerts a long-lasting effect on BAT. Collectively, these findings indicate the importance of nutrition during pregnancy with respect to the energy metabolism of the offspring, and pregnant women should thus ensure proper nutrition during pregnancy to ensure normal energy metabolism in the offspring.

Candidate biomarkers in brown adipose tissue for post-mortem diagnosis of fatal hypothermia.

Post-mortem diagnosis of fatal hypothermia (FHT) is challenging in forensic practice because traditional morphological and biochemical methods lack specificity. Recent studies have reported that brown adipose tissue (BAT) is activated during cold-induced non-shivering thermogenesis in mammals, but BAT has not been used to diagnose FHT. The aim of this study was to identify novel biomarkers in BAT for FHT based on morphological changes and differential protein expression. Two FHT animal models were created by exposing mice to 4 or -20 °C at 50% humidity. Morphologically, the unilocular lipid droplet content was significantly increased in BAT of FHT model mice compared with that of control mice. Proteomics analysis revealed a total of 283 and 266 differentially expressed proteins (DEPs) between the 4 or -20 °C FHT subgroups and control group, respectively. In addition, 140 proteins were shared between the FHT subgroups. GO and KEGG analyses revealed that the shared DEPs were mainly enriched in pathways associated with metabolism, oxidative phosphorylation, and thermogenesis. Further screening (|log2FC| > 1.6, q-value (FDR) < 0.05) identified GMFB, KDM1A, DDX6, RAB1B, SHMT-1, CLPTM1, and LMF1 as candidate biomarkers of FHT. Subsequent validation experiments were performed in FHT model mice using classic immunohistochemistry and western blotting. RAB1B and GMFB expression was further verified in BAT specimens from human cases of FHT. The results demonstrate that BAT can be used as a target organ for FHT diagnosis employing RAB1B and GMFB as biological markers, thus providing a new strategy for the post-mortem diagnosis of FHT in forensic practice.

High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome

SummaryDiets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

AIFM2 Is Required for High-Intensity Aerobic Exercise in Promoting Glucose Utilization.

Skeletal muscle is a major regulator of glycemic control at rest, and glucose utilization increases drastically during exercise. Sustaining a high glucose utilization via glycolysis requires efficient replenishment of NAD+ in the cytosol. Apoptosis-inducing mitochondrion-associated factor 2 (AIFM2) was previously shown to be a NADH oxidoreductase domain-containing flavoprotein that promotes glycolysis for diet and cold-induced thermogenesis. Here, we find that AIFM2 is selectively and highly induced in glycolytic extensor digitorum longus (EDL) muscle during exercise. Overexpression (OE) of AIFM2 in myotubes is sufficient to elevate the NAD+-to-NADH ratio, increasing the glycolytic rate. Thus, OE of AIFM2 in skeletal muscle greatly increases exercise capacity, with increased glucose utilization. Conversely, muscle-specific Aifm2 depletion via in vivo transfection of hairpins against Aifm2 or tamoxifen-inducible haploinsufficiency of Aifm2 in muscles decreases exercise capacity and glucose utilization in mice. Moreover, muscle-specific introduction of NDE1, Saccharomyces cerevisiae external NADH dehydrogenase (NDE), ameliorates impairment in glucose utilization and exercise intolerance of the muscle-specific Aifm2 haploinsufficient mice. Together, we show a novel role for AIFM2 as a critical metabolic regulator for efficient utilization of glucose in glycolytic EDL muscles.

Cold-sensitive ventromedial hypothalamic neurons control homeostatic thermogenesis and social interaction-associated hyperthermia

Homeostatic thermogenesis is an essential protective feature of endotherms. However, the specific neuronaltypes involved in cold-induced thermogenesis remain largely unknown. Using functional magneticresonance imaging and in situ hybridization, we screened for cold-sensitive neurons and found preprodynorphin (PDYN)-expressing cells in the dorsal medial region of the ventromedial hypothalamus (dmVMH) to be a candidate. Subsequent invivo calcium recording showed that cold temperature activates dmVMHPdynneurons, whereas hot temperature suppresses them. In addition, optogenetic activation of dmVMHPdyn neurons increases the brown adipose tissue and core body temperature, heart rate, and blood pressure, whereas optogenetic inhibition shows opposite effects, supporting their role in homeostatic thermogenesis. Furthermore, we found that dmVMHPdynneurons are linked to known thermoregulatory circuits. Importantly, dmVMHPdynneurons also show activation during mouse social interaction, and optogenetic inhibition suppresses social interaction and associated hyperthermia. Together, our study describes dual functions of dmVMHPdynneurons that allow coordinated regulation of body temperature and social behaviors.

COLD INDUCES EXPRESSION OF GENES SPECIFIC TO THERMOGENESIS (PGC-1α, UCP1) AND BEIGE CELLS (TMEM26, SLC27A1) IN MOUSE INGUINAL WHITE ADIPOSE TISSUE

Studying adaptive thermogenic responses as being a strategy to protect against several metabolic disorders. The browning process is a crucial point of adaptive thermogenic responses. The present study was carried out to examine whether inguinal white adipose tissue (iWAT) is a candidate for the browning process. Mice were caged in a 4 °C cold chamber (Cold group) for 24 hours and 23 °C room temperature condition (RT group). The result showed that mRNA expression of genes specific to thermogenesis, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and uncoupling protein 1 (UCP1), was markedly upregulated in iWAT of the mice in the Cold group compared to the mice in the RT group. Consistent with this, mRNA expression of the Transmembrane protein 26 (TMEM26) gene, specific to beige cells, was also significantly higher in the iWAT of the cold exposed mice than that in the iWAT of the mice housed at room temperature. Expression of solute carrier family 27member 1 (SLC27A1) gene, another gene coding for a protein of beige cells, was tendency to increase in iWAT of the cold exposed mice compared with that in iWAT of the control mice. However, this change was not significantly differed between the two groups. These data demonstrate that iWAT is an important tissue responding to cold-induced thermogenesis and browning process. Thus, iWAT is a promising candidate for further studies on the mechanism of cold-induced thermogenic responses in white adipose tissues.

DDB1 prepares brown adipocytes for cold-induced thermogenesis

Abstract Brown adipose tissue (BAT) plays a key role in thermogenesis during acute cold exposure. However, it remains unclear how BAT is prepared to rapidly turn on thermogenic genes. Here, we show that damage-specific DNA binding protein 1 (DDB1) mediates the rapid transcription of thermogenic genes upon acute cold exposure. Adipose- or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes. These mice develop hypothermia when subjected to acute cold exposure at 4 °C and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation. Mechanistically, DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b (P-TEFb) to release promoter-proximally paused RNA polymerase II (Pol II), thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure. Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.

Intraindividual difference between supraclavicular and subcutaneous proton density fat fraction is associated with cold-induced thermogenesis

Brown adipose tissue (BAT) activity is triggered by cold exposure resulting in an increased resting energy expenditure, called cold-induced non-shivering thermogenesis (CIT). Magnetic resonance (MR)-based proton density fat fraction (PDFF) of the supraclavicular fossa has been proposed as a surrogate marker of human BAT. The present study investigates supraclavicular PDFF in relation to CIT. For this prospective cross-sectional study 39 adults were recruited, from a cross-sectional study, exploring energy expenditure after cold exposure compared to thermoneutral conditions. Participants underwent additional MR examination of neck, pelvis, and abdomen. Supraclavicular and subcutaneous gluteal adipose tissue depots were segmented semi-automatically. Mean PDFF was assessed for each compartment and the delta PDFF was calculated as the difference of both. Correlation analysis of supraclavicular PDFF to CIT was performed for the whole cohort and subgroups, sorted by body mass index (BMI) and body fat percentage. Median age of participants (61.5% female) was 27 years. BMI ranged from 19.0 to 38.5 kg/m2, with body fat percentages from 4.6% to 45.3%. Median supraclavicular PDFF of 82.5% and median gluteal PDFF of 91.1%, were significantly different (P<0.0001). Median delta PDFF was 8.8% (3.9-21.9%). Mean CIT was 4.7%±9.0%. No statistically significant correlation of supraclavicular PDFF and CIT was found in the whole cohort and in most of the observed subgroups. Just the subgroup with normal body fat percentage revealed significant correlations between supraclavicular PDFF and CIT (rho =-0.59; P=0.003). Delta PDFF was significantly associated with CIT (rho =0.36; P=0.026). PDFF is influenced by adiposity. Therefore, if supraclavicular PDFF is used as approach to indirectly assess BAT presence, body composition should be considered. Delta PDFF, as the difference between gluteal and supraclavicular PDFF, may be a marker of CIT.

Correction: FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis.

There were errors in Development (2022) 149, dev200260 (doi:10.1242/dev.200260).The location labels in Fig. 3D were incorrect. The corrected and original panels are shown below.The legend for Fig. 7B quoted an incorrect target number. The corrected and original legends are shown below.Fig. 7. (corrected). FOXP4 directly regulates the expression of Cebpb and Pgc1a during beige adipocyte thermogenic activation. (B) Heatmap of the 22 putative FOXP4-targeted gene expressions from the experiment shown in A. Chromatin occupancy analysis of ChIP-seq was conducted for SVF-derived beige adipocytes with an anti-Foxp4 antibody and 22 common targets were detected to overlap with RNA-seq results.Fig. 7. (original). FOXP4 directly regulates the expression of Cebpb and Pgc1a during beige adipocyte thermogenic activation. (B) Heatmap of the 22 putative FOXP4-targeted gene expressions from the experiment shown in A. Chromatin occupancy analysis of ChIP-seq was conducted for SVF-derived beige adipocytes with an anti-Foxp4 antibody. Five common targets were detected to overlap with RNA-seq results.In Fig. S6C, the heatmap was incorrect. The corrected and original figures are shown below.In Fig. S8, a panel was removed, so both the figure and legend have been updated. The corrected and original figures are shown below.Also, some values for n have been replaced in the updated Supplementary information.Fig. S3BCorrected(B) Assessment of Foxp4 mRNA expression in BAT and sWAT from mice by qPCR. n, 3∼5.Original(B) Assessment of Foxp4 mRNA expression in BAT and sWAT from mice by qPCR. n, 3.Fig S3HCorrected(H) Oxygen consumption rate (OCR) was measured for brown adipocytes from (F). Uncoupled respiration was recorded after oligomycin inhibition of 1 ATP synthesis, and maximal respiration following stimulation with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). n, 7.Original(H) Oxygen consumption rate (OCR) was measured for brown adipocytes from (F). Uncoupled respiration was recorded after oligomycin inhibition of ATP synthesis, and maximal respiration following stimulation with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). n, 3.Fig S3ICorrected(I) Quantitative analysis of basal and uncoupled OCR in (H). n, 7.Original(I) Quantitative analysis of basal and uncoupled OCR in (H). n, 3.Fig S7B,DCorrected(B,D) qPCR analysis for thermogenic gene expressions in BAT (B) and sWAT (D) from CL-316,243-stimulated mice. n, 3.Original(B,D) qPCR analysis for thermogenic gene expressions in BAT (B) and sWAT (D) from CL-316,243-stimulated mice. n, 5.Both the online full text and PDF versions of the paper have been corrected. We apologise to the readers for these errors and any inconvenience they may have caused.

Systematic Analysis of the Molecular Mechanisms of Cold and Hot Properties of Herbal Medicines.

Effective treatments for patients experiencing temperature-related symptoms are limited. The hot and cold effects of traditional herbal medicines have been utilized to treat and manage these symptoms, but their molecular mechanisms are not fully understood. Previous studies with arbitrarily selected herbs and ingredients may have produced biased results. Here, we aim to systematically elucidate the molecular mechanisms of the hot and cold properties of herbal medicines through an unbiased large-scale investigation of herbal ingredients, their target genes, and the transcriptome signatures induced by them. Using data regarding 243 herbs retrieved from two herbal medicine databases, we statistically identify (R)-Linalool, (-)-alpha-pinene, peruviol, (L)-alpha-terpineol, and cymol as five new hot-specific ingredients that share a common target, a norepinephrine transporter. However, no significant ingredients are cold-specific. We also statistically identify 14 hot- and 8 cold-specific new target genes. Pathway enrichment analysis of hot-specific target genes reveals the associated pathways including neurotransmitter reuptake, cold-induced thermogenesis, blood pressure regulation, adrenergic receptor signaling, and cation symporter activity. Cold-specific target genes are associated with the steroid pathway. Transcriptome analysis also shows that hot herbs are more strongly associated with coagulation and synaptic transmission than cold herbs. Our results, obtained from novel connections between herbal ingredients, target genes, and pathways, may contribute to the development of pharmacological treatment strategies for temperature-related pain using medicinal plants.

FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis.

Beige adipocytes have a discrete developmental origin and possess notable plasticity in their thermogenic capacity in response to various environmental cues, but the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, forkhead box P4 (FOXP4), that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis capacity upon cold exposure. Of note, the outcome of Foxp4 deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we suggest that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program.

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.

Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.

Reactive oxygen species (ROS) activate uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, the endogenous regulator of ROS in activated BAT and its role in pathological conditions remain unclear. We show that serum levels of selenoprotein P (SeP; encoded by SELENOP) negatively correlate with BAT activity in humans. Physiological cold exposure downregulates Selenop in BAT. Selenop knockout mice show higher rectal temperatures and UCP1 sulfenylation during cold exposure. SeP treatment to brown adipocytes eliminated the NA-induced mitochondrial ROS by upregulating glutathione peroxidase 4 and impaired cellular thermogenesis. A high-fat/high-sucrose diet elevates serum SeP levels and diminishes the elevated NA-induced thermogenesis in BAT-Selenop KO mice. Therefore, SeP is the intrinsic factor inducing reductive stress that impairs thermogenesis in BAT and may be a potential therapeutic target for obesity and diabetes.

From the Literature

From the Literature

Cold-Induced Thermogenesis Shows a Diurnal Variation That Unfolds Differently in Males and Females.

ContextCold exposure mobilizes lipids to feed thermogenic processes in organs, including brown adipose tissue (BAT). In rodents, BAT metabolic activity exhibits a diurnal rhythm, which is highest at the start of the wakeful period.ObjectiveWe investigated whether cold-induced thermogenesis displays diurnal variation in humans and differs between the sexes.MethodsThis randomized crossover study included 24 young and lean male (n = 12) and female (n = 12) participants who underwent 2.5-hour personalized cooling using water-perfused mattresses in the morning (7:45 am) and evening (7:45 pm), with 1 day in between. We measured energy expenditure (EE) and supraclavicular skin temperature in response to cold exposure.ResultsIn males, cold-induced EE was higher in the morning than in the evening (+54% ± 10% vs +30% ± 7%; P = 0.05) but did not differ between morning and evening in females (+37% ± 9% vs +30% ± 10%; P = 0.42). Only in males, supraclavicular skin temperature upon cold increased more in morning than evening (+0.2 ± 0.1 °C vs −0.2 ± 0.2 °C; P = 0.05). In males, circulating free fatty acid (FFA) levels were increased after morning cold exposure, but not evening (+90% ± 18% vs +9% ± 8%; P < 0.001). In females, circulating FFA (+94% ± 21% vs +20% ± 5%; P = 0.006), but also triglycerides (+42% ± 5% vs +29% ± 4%, P = 0.01) and cholesterol levels (+17% ± 2% vs 11% ± 2%; P = 0.05) were more increased after cold exposure in morning than in evening.ConclusionCold-induced thermogenesis is higher in morning than evening in males; however, lipid metabolism is more modulated in the morning than the evening in females.

Evaluation of thermal sensitivity is of potential clinical utility for the predictive, preventive, and personalized approach advancing metabolic syndrome management

A possible association between metabolic disorders and ambient temperature has been suggested, and cold exposure as a way of increasing energy expenditure has gained considerable interest for preventative/therapeutic measures toward metabolic disorders. Although thermal sensitivity, which has recently been studied in regard to its utility as a risk assessment/patient stratification for various diseases, might influence physiological responses to ambient temperature on an individual basis, more studies are needed. We aimed to investigate the association between self-identified thermal intolerance/sensation and metabolic syndrome (MetS) to verify the working hypothesis that individuals with altered thermal sensitivity may have a predisposition to MetS. We fitted generalized additive models for thermal intolerance/sensation using body mass index (BMI) and waist–hip ratio in women, and identified those with higher/lower thermal intolerance/sensation than those predicted by the models. Higher heat intolerance, higher heat sensation, and lower cold intolerance were associated with a higher prevalence of MetS. The risk of having MetS was increased in those who had two or three associated conditions compared with those with none of these conditions. In an analysis for MetS components, significant associations of thermal sensitivity were present with high glucose, triglyceride, and blood pressure levels. Overall, higher heat intolerance/sensation and lower cold intolerance were associated with increased prevalence of MetS even at a similar level of obesity. Our study indicates that evaluation of thermal sensitivity may help identify individuals at high risk for MetS, and lead to more advanced patient stratification and personalized treatment strategies for MetS, including cold-induced thermogenesis.

Integrated proteome and phosphoproteome analysis of interscapular brown adipose and subcutaneous white adipose tissues upon high fat diet feeding in mouse

Thermogenesis is a promising approach to limit weight gain in response to excess nutrition. In contrast to cold-induced thermogenesis, the molecular and cellular mechanisms of diet-induced thermogenesis (DIT) have not been fully characterized. Here, we explored the response of brown adipose tissue (BAT) and subcutaneous white adipose tissue (sWAT) to high fat diet (HFD) using proteome and phosphoproteome analysis. We observed that after HFD, Uncoupling protein 1 (UCP1) and its phosphorylation were only increased in BAT. Furthermore, proteins involved in fatty acid oxidation, tricarboxylic acid cycle, and oxidative phosphorylation were also upregulated in BAT. Nevertheless, most metabolic related proteins were downregulated in sWAT. We found that these metabolic changes accompanied with different variation of mitochondrial proteins between BAT and sWAT. After HFD, most mitochondrial proteins were decreased in sWAT, but not in BAT. This effect was correlated with decreased mitochondrial ribosomal proteins in sWAT. Finally, through phosphoproteomic analysis, we predicted the activities of kinases in HFD mice and observed that there were more kinases inactivated in sWAT. Finally, this dataset provides a valuable resource for molecular researchers in the fields of obesity and obesity-related disease. SignificanceThermogenesis is a promising approach to combat obesity in response to excess energy. Nevertheless, the molecular and cellular mechanisms of DIT have not been fully characterized. Herein, we employed mass spectrometry (MS)-based proteomics and phosphoproteomics to identify differentially regulated proteins and phosphosites in BAT and sWAT of mice fed with HFD. This study unveils the differential regulatory networks of HFD in BAT and sWAT, which provides reference omics data to future researchers.

Effect of BMI on the Thermogenic Response to Cold Exposure and Associated Changes in Metabolism and Browning Markers in Adult Humans

Introduction: Brown adipose tissue (BAT) serves to produce heat by nonshivering thermogenesis. Activation of BAT increases energy expenditure and is seen as a putative strategy to treat obesity. There are conflicting data on the capacity for cold-induced thermogenesis in individuals with higher BMI. Methods: To investigate the effect of BMI on cold-induced stimulation of energy expenditure, changes in the metabolic profile, and the expression of browning markers in subcutaneous white adipose tissue (scWAT), healthy adults (N = 173, 50.9% females) with a median age of 26.0 (interquartile range [IQR]: 23.0; 28.0) years and a median body mass index (BMI) of 23.6 [IQR: 21.9; 26.6] kg/m² were exposed to short-term mild cold exposure (CE). Resting energy expenditure (REE) was measured by indirect calorimetry and blood sampling was conducted at baseline and after CE. In a subgroup of participants with obesity, subcutaneous abdominal fat biopsies were taken before and after CE. Results: The cold-induced median increase in REE was 74 (IQR: −28; 241) kcal/day (p < 0.001). This increase negatively correlated with BMI (p < 0.001). Participants with BMI 18.5–24.9 kg/m² displayed a significant median increase of 103 kcal/day (p < 0.001), participants with overweight or obesity were not able to increase REE (23, p = 0.468 or −30 kcal/day, p = 0.917, respectively). In participants with obesity, expression of cell death activator in scWAT after CE was upregulated in females (p = 0.034). Conclusions: Persons with overweight and obesity do not increase REE in response to CE, presumably reflecting lower BAT activity. Likewise, the metabolic response to cold is diminished in participants with elevated BMI.