Natural killer cell functional genetics and donor-specific antibody-triggered microvascular inflammation.

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], rs9916629-C/T). Fifty patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2wt/del recipients; P = .001) and remained significant in a proportional odds multivariable model (odds ratio, 7.84; 95% confidence interval, 2.37-30.47; P = .001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.

Morphologic and Molecular Features of Antibody-Mediated Transplant Rejection: Pivotal Role of Molecular Injury as an Independent Predictor of Renal Allograft Functional Decline.

Current knowledge about the factors correlating with functional decline and subsequent failure of kidney allografts in antibody-mediated rejection (ABMR) is limited. We conducted a cohort study involving 75 renal allograft recipients diagnosed with late ABMR occurring at least 6 months after transplantation. The study aimed to examine the correlation of molecular and histologic features with estimated glomerular filtration rate (eGFR) trajectories and death-censored graft survival. We focused on sum scores reflecting histologic ABMR activity versus chronicity and molecular scores of ABMR probability (ABMRProb), injury-repair response (IRRAT) and fibrosis (ciprob). In multivariable Cox analysis, a Banff lesion-based chronicity index (ci+ct+cg[x2]; hazard ratio per interquartile range [IQR]: 1.97 [95% confidence interval: 0.97 to 3.99]) and IRRAT (1.93 [0.96 to 3.89]) showed the strongest associations with graft failure. Among biopsy variables, IRRAT exhibited the highest relative variable importance and emerged as the sole independent predictor of eGFR slope (change per IQR: -4.2 [-7.8 to -0.6] mL/min/1.73 m2/year). In contrast, morphologic chronicity associated with baseline eGFR only. We conclude that the extent of molecular injury is a robust predictor of renal function decline. Transcriptome analysis has the potential to improve outcome prediction and possibly identify modifiable injury, guiding targeted therapeutic interventions.

Obesity is associated with a higher Torque Teno viral load compared to leanness.

Introduction: Obesity affects a rising proportion of the population and is an important risk factor for unfavorable outcomes in viral disease including severe acute respiratory syndrome coronavirus 2- associated diseases. Torque Teno virus (TTV) is a ubiquitous and apathogenic virus which reflects the immune function of its host. The aim of this study was to investigate the association between obesity and TTV load - an indirect marker of compromised viral immune response. Methods: TTV was quantified by TTV R-GENE® PCR in a total of 89 participants of which 30 were lean (BMI <25 kg/m2) and 59 were obese (BMI >30 kg/m2). For 38 subjects, follow-up was available after bariatric surgery. Results: TTV load was higher in individuals with obesity (median 2.39, IQR: 1.69-3.33 vs. 1.88, IQR 1.08-2.43 log10 copies/mL; p = 0.027). Multivariable linear modeling revealed an independent association between TTV load and obesity. TTV was positively correlated with waist-to-hip ratio and inversely with 25OH vitamin D levels. Interleukin 6 and fasting insulin resistance were confounders of the association between TTV and obesity, while age was an effect modifier. TTV load increased by 87% (95% CI 2-243%) in the year following bariatric surgery. Discussion: A higher TTV load in obese individuals may reflect compromised immune function and thus might serve for risk stratification of unfavorable outcomes during infectious disease, including coronavirus disease 2019, in this population. Our data warrant further analysis of TTV-based risk assessment in obese individuals in the context of infectious disease-associated outcomes.

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.

High-Density Lipoprotein Particle Subclasses in Statin-Treated Patients with Peripheral Artery Disease Predict Long-Term Survival.

Low-density lipoprotein-cholesterol reduction showed a strong reduction of cardiovascular (CV) event rates in CV disease. However, the residual risk of future CV events remains high, which especially extends to peripheral arterial disease (PAD). Nuclear magnetic resonance (NMR) spectroscopy offers a novel method for analysis of the lipoprotein spectrum. This study investigates lipoprotein subclasses using NMR spectroscopy and assesses implications for long-term survival in PAD. NMR spectroscopy was performed by Nightingale Inc., in 319 patients with stable PAD and well-controlled CV risk factors. Patients were followed-up for 10 years. During that period, 123 patients (38.5%) died, of those 68 (21.3%) were defined as CV deaths. Outcome data were analyzed by the Kaplan-Meier method and multivariable Cox-regression for lipoprotein particles. Small and medium high-density lipoprotein-particles (S-HDL-P and M-HDL-P) showed a significant inverse association with all-cause mortality in Cox-regression analyses after multivariable adjustment (S-HDL-P, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.57-0.88; M-HDL-P, HR: 0.72, 95% CI: 0.58-0.90) for each increase of one standard deviation. In contrast, cholesterol-rich X-large HDL-particles (XL-HDL-P) showed a positive association with all-cause mortality (HR: 1.51, 95% CI: 1.20-1.89). Only the association between XL-HDL-P and CV death sustained multivariable adjustment (HR: 1.49, 95% CI: 1.10-2.02), whereas associations for S-HDL-P and M-HDL-P were attenuated (HR: 0.76, 95% CI: 0.57-1.01; HR: 0.80, 95% CI: 0.60-1.06). This study shows a novel association for a beneficial role of S-HDL-P and M-HDL-P but a negative association with higher cholesterol-rich XL-HDL-P for long-term outcome in well-treated patients with PAD. Thus, these results provide evidence that NMR-measured HDL particles identify patients at high CV residual risk beyond adequate lipid-lowering therapy.

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome.

Natural killer (NK) cells may contribute to antibody-mediated rejection (ABMR) of renal allografts. The role of distinct NK cell subsets in this specific context, such as NK cells expressing the activating receptor NKG2C, is unknown. Our aim was to investigate whether KLRC2 gene deletion variants which determine NKG2C expression affect the pathogenicity of donor-specific antibodies (DSA) and, if so, influence long-term graft survival. We genotyped the KLRC2wt/del variants for two distinct kidney transplant cohorts, (i) a cross-sectional cohort of 86 recipients who, on the basis of a positive post-transplant DSA result, all underwent allograft biopsies, and (ii) 1,860 recipients of a deceased donor renal allograft randomly selected from the Collaborative Transplant Study (CTS) database. In the DSA+ patient cohort, KLRC2wt/wt (80%) was associated with antibody-mediated rejection (ABMR; 65% versus 29% among KLRC2wt/del subjects; P=0.012), microvascular inflammation [MVI; median g+ptc score: 2 (interquartile range: 0-4) versus 0 (0-1), P=0.002], a molecular classifier of ABMR [0.41 (0.14-0.72) versus 0.10 (0.07-0.27), P=0.001], and elevated NK cell-related transcripts (P=0.017). In combined analyses of KLRC2 variants and a functional polymorphism in the Fc gamma receptor IIIA gene (FCGR3A-V/F158), ABMR rates and activity gradually increased with the number of risk genotypes. In DSA+ and CTS cohorts, however, the KLRC2wt/wt variant did not impact long-term death-censored graft survival, also when combined with the FCGR3A-V158 risk variant. KLRC2wt/wt may be associated with DSA-triggered MVI and ABMR-associated gene expression patterns, but the findings observed in a highly selected cohort of DSA+ patients did not translate into meaningful graft survival differences in a large multicenter kidney transplant cohort not selected for HLA sensitization.

Active Brown Adipose Tissue is Associated With a Healthier Metabolic Phenotype in Obesity.

Obesity is associated with increasing cardiometabolic morbidity and mortality worldwide. Not everyone with obesity, however, develops metabolic complications. Brown adipose tissue (BAT) has been suggested as a promoter of leanness and metabolic health. To date, little is known about the prevalence and metabolic function of BAT in subjects with severe obesity, a population at high cardiometabolic risk. In this cross-sectional study, we included 40 individuals with WHO class II-III obesity (BMI ≥ 35 kg/m2). Employing a 150-minute personalized cooling protocol and 18F-fluorodeoxyglucose positron emission tomography/computed tomography, cold-activated BAT was detectable in 14 (35%) of the participants. Cold-induced thermogenesis was significantly higher in participants with detectable BAT compared to those without. Notably, individuals with obesity and active BAT had 28.8% lower visceral fat mass despite slightly higher total fat mass compared to those without detectable BAT 18F-FDG uptake. This was accompanied by lower insulin resistance and systemic inflammation and improved NAFLD parameters, all adjusted for age, sex, and percent body fat. Contrary to previous assumptions, we show here that a significant fraction of individuals with severe obesity has active BAT. We found that decreased BAT 18F-FDG uptake was not associated with adiposity per se but with higher visceral fat mass. In summary, active BAT is linked to a healthier metabolic phenotype in obesity.

Characterization of endogenous bile acid composition in individuals with cold-activated brown adipose tissue.

INTRODUCTION: Bile acid signaling has been suggested to promote BAT activity in various experimental models. However, little is known if and how physiologic bile acid metabolism is linked to BAT function in humans. Here we investigated the association between BAT activity and circulating bile acid concentrations in lean and obese individuals. METHODS: BAT 18F-fluorodeoxyglucose uptake was measured after a standardized cooling protocol by positron emission tomography/computed tomography. Cold-induced thermogenesis was assessed by indirect calorimetry. Fasting bile acid concentrations were determined by high performance liquid chromatography-high-resolution mass spectrometry. RESULTS: In a cohort of 24 BAT-negative and 20 BAT-positive individuals matched by age, sex, and body mass index, circulating bile acid levels were similar between groups except for higher ursodeoxycholic acid and a trend towards a lower 12α-OH/non-12α-OH bile acid ratio in lean participants with active BAT compared to those without. Moreover, the 12α-OH/non-12α-OH ratio, a marker of CYP8B1 activity, correlated negatively with BAT volume and activity. CONCLUSION: Fasting concentrations of major bile acids are not associated with cold-induced BAT activity in humans. However, the inverse association between BAT activity and 12α-OH/non-12α-OH ratio may suggest CYP8B1 as a potential new target in BAT function and warrants additional investigation.

Sex differences in brown adipose tissue activity and cold-induced thermogenesis.

INTRODUCTION: Brown adipose tissue (BAT) is suggested to exhibit a sexual dimorphism and thus contributes to the observed sex differences in cardiometabolic risk observed between women and men. Clinical data supporting this hypothesis are however scarce. The aim of this study was to investigate the relationship between BAT activity and sex using positron emission tomography (PET) - the current gold-standard for BAT quantification. METHODS: In this study, we included 95 subjects with a wide BMI range (20-55 kg/m2) aged from 18 to 50 years. Avoiding shivering, participants were cooled with a water-perfused vest to achieve adequate BAT activation. BAT activity was determined by 18F-fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT). Cold-induced thermogenesis (CIT) was quantified by indirect calorimetry. RESULTS: BAT was present in 44.6% of pre-menopausal women and in 35.9% of men (p = 0.394). CIT was significantly higher in women (p = 0.024). Estradiol levels were positively associated with CIT independent of age, sex, body fat and other sex hormones (b = 0.360, p = 0.016). In women, CIT decreased during the menstrual cycle, with lower levels in the luteal phase similar to median concentrations in men. CONCLUSION: The prevalence of cold-activated BAT is slightly but non-significantly higher in pre-menopausal women than men. CIT is increased in females and independently associated with estradiol, suggesting that sex hormones may play a role in different thermogenic responses between men and women.

Decrease of dipeptidyl peptidase 4 activity is associated with weight loss after bariatric surgery.

PURPOSE: Dipeptidyl peptidase 4 (DPP4) is expressed and secreted by adipocytes. DPP4 induces insulin resistance independently of its effect on glucagon-like peptide 1, thus it is conceivable that DPP4 directly contributes to metabolic dysfunction in patients with morbid obesity. The aim of this study was to investigate the impact of weight loss induced by bariatric surgery on DPP4 activity, and whether these changes are associated with improvements in markers of metabolic dysfunction and fatty liver disease. MATERIALS AND METHODS: We included 68 non-diabetic patients who underwent bariatric surgery. Serum DPP4 activity was measured using a fluorogenic substrate before and after surgery. RESULTS: Results: After a median follow-up period of 12 (IQR 11-17) months, median serum DPP4 activity decreased from 230 (IQR: 194-273) to 193 (164-252) pmol/min (p=0.012). The decrease in DPP4 activity was significantly correlated with decreases in BMI, improved cholesterol levels, reduced hepatic injury markers as well as improved post-prandial insulin sensitivity. After multivariable adjustment, ΔDPP4 activity remained significantly associated with Δcholesterol (beta=0.341, p=0.025), ΔLDL cholesterol (beta=0.350, p=0.019), Δgamma-glutamyltransferase (beta=0.323, p=0.040) and ΔMatsuda index (beta=-0.386, p=0.045). CONCLUSION: We demonstrated that weight loss induced by bariatric surgery results in decreased circulating DPP4 activity beyond the initial phase of weight loss. The associations between decreased DPP4 activity and improved cholesterol levels as well as hepatic injury markers point towards pleiotropic effects of DPP4 beyond glucose metabolism which warrant further investigation.

Discovery of melanin-concentrating hormone receptor 1 in brown adipose tissue.

Although extensive research on brown adipose tissue (BAT) has stimulated optimism in the battle against obesity and diabetes, BAT physiology and organ crosstalk are not fully understood. Besides BAT, melanin-concentrating hormone (MCH) and its receptor (MCHR1) play an important role in energy homeostasis. Because of the link between hypothalamic MCH neurons and sympathetic BAT activation via ß-adrenoceptors, we investigated the expression and physiological role of the MCHR1 in BAT. MCHR1 was detected in rodent and human BAT with RT-qPCR and western blot analyses. In vivo imaging in rats used the glucose analog [18 F]FDG and the MCHR1-tracer [11 C]SNAP-7941. We found that the ß3-adrenoceptor (ADRB3) agonist CL316,243 increased [11 C]SNAP-7941 uptake in BAT. Additionally, a pharmacological concentration of SNAP-7941-a low-affinity ADRB3 ligand-stimulated [18 F]FDG uptake, reflecting BAT activation. In cultured human adipocytes, CL316,243 induced MCHR1 expression, further supporting a direct interaction between MCHR1 and ADRB3. These findings characterized MCHR1 expression in rodent and human BAT for the first time, including in vitro and in vivo data demonstrating a link between MCHR1 and the ß3-adrenergic system. The presence of MCHR1 in BAT emphasizes the role of BAT in energy homeostasis and may help uncover treatment approaches for obesity.

GlycA for long-term outcome in T2DM secondary prevention.

AIMS: Glycosylated acetyls (GlycA), a systemic marker of inflammation, were associated both with incident type 2 diabetes mellitus (T2DM) and incident cardiovascular (CV) disease. This study evaluates the predictive value of GlycA for long-term survival in patients with T2DM and peripheral artery disease (PAD). METHODS: GlycA (mmol/l) levels were measured by nuclear magnetic resonance spectroscopy in a cross-sectional cohort of patients with PAD (n = 319). Both all-cause and CV mortality were evaluated after a follow-up of 9.0 (IQR 6.5-9.5) years. During the follow-up 117 patients died, of those 64 events were of CV origin (PAD-T2DM subgroup: all-cause mortality n = 60, CV-mortality n = 32). RESULTS: PAD-T2DM showed a tendency towards a worse CV risk factor profile and a higher percentage of known coronary artery disease (24.9% vs 43.5%, p < 0.001). GlycA levels were higher in PAD-T2DM (1.6 ± 0.2 vs. 1.53 ± 0.18, p = 0.002). GlycA predicted all-cause mortality after multivariable adjustment for traditional CV risk factors (HR for 1 SD increase 1.51, 95% confidence interval 1.03-2.19) in PAD-T2DM, while no association could be seen with CV-mortality (1.22, 0.73-2.06). CONCLUSIONS: GlycA was capable of predicting long-term outcome in PAD patients with T2DM. Thus, GlycA might reflect the added inflammatory burden of T2DM in systemic atherosclerosis.

The Transcriptional Role of Vitamin A and the Retinoid Axis in Brown Fat Function.

In recent years, brown adipose tissue (BAT) has gained significance as a metabolic organ dissipating energy through heat production. Promotion of a thermogenic program in fat holds great promise as potential therapeutic tool to counteract weight gain and related sequelae. Current research efforts are aimed at identifying novel pathways regulating brown fat function and the transformation of white adipocytes into BAT-like cells, a process called "browning." Besides numerous genetic factors some circulating molecules can act as mediators of adipose tissue thermogenesis. Vitamin A metabolites, the retinoids, are potent regulators of gene transcription through nuclear receptor signaling and are thus involved in a plethora of metabolic processes. Accumulating evidence links retinoid action to brown fat function and browning of WAT mainly via orchestrating a transcriptional BAT program in adipocytes including expression of key thermogenic genes such as uncoupling protein 1. Here we summarize the current understanding how retinoids play a role in adipose tissue thermogenesis through transcriptional control of thermogenic gene cassettes and potential non-genomic mechanisms.

Predictive power of novel and established obesity indices for outcome in PAD during a five-year follow-up.

BACKGROUND AND AIMS: Previous data show contradicting results regarding relevance of obesity on outcome in peripheral arterial disease (PAD). Thus, this study aims to evaluate the predictive power of obesity as measured by established and novel obesity indices (waist circumference WC, waist-hip ratio WHR, body-mass index BMI, body adiposity index BAI, visceral adiposity index VAI, weight-adjusted waist index WWI) in a PAD cohort. METHODS AND RESULTS: In 367 patients with diagnosed PAD anthropometric parameters were assessed at study inclusion in an observational study. Mortality data was retrieved from the central death registry after five years. Outcome analyses were performed by multivariable Cox-regression models. 57 PAD patients (15.5%) died during the follow-up, of those 36 were categorized as cardiovascular origin. Patients from the all-cause mortality group were older, more often diabetics with a worse glucose control and had worse renal function. Obesity indices were not significantly different between the event and control group. None of the evaluated risk factors predicted cardiovascular or all-cause death after multivariable adjustment for age, gender, LDL-C, serum creatinine, systolic blood pressure, CRP, smoking habits, diabetes status and previous history of peripheral revascularisation (all-cause WC 1.007 (0.983-1.031), WHR 1.772 (0.106-29.595), BMI 1.006 (0.939-1.078), BAI 1.002 (0.945-1.063), VAI 1.019 (0.895-1.161), WWI 1.085 (0.831-1.416); cv-death WC 1.007 (0.978-1.036), WHR 0.382 (0.006-25.338), BMI 1.004 (0.918-1.098), BAI 1.034 (0.959-1.116), VAI 1.036 (0.885-1.213), WWI 1.061 (0.782-1.441)). CONCLUSION: Obesity as risk marker estimated by indices both for general and visceral adiposity, does not predict mortality in a secondary prevention cohort of PAD patients.

The Presence of Active Brown Adipose Tissue Determines Cold-Induced Energy Expenditure and Oxylipin Profiles in Humans.

BACKGROUND: Accumulating evidence links brown adipose tissue (BAT) to increased cold-induced energy expenditure (CIEE) and regulation of lipid metabolism in humans. BAT has also been proposed as a novel source for biologically active lipid mediators including polyunsaturated fatty acids (PUFAs) and oxylipins. However, little is known about cold-mediated differences in energy expenditure and various lipid species between individuals with detectable BAT positive (BATpos) and those without BAT negative (BATneg). METHODS: Here we investigated a unique cohort of matched BATpos and BATneg individuals identified by 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography ([18F]-FDG PET/CT). BAT function, CIEE, and circulating oxylipins, were analyzed before and after short-term cold exposure using [18F]-FDG PET/CT, indirect calorimetry, and high-resolution mass spectrometry, respectively. RESULTS: We found that active BAT is the major determinant of CIEE since only BATpos individuals experienced significantly increased energy expenditure in response to cold. A single bout of moderate cold exposure resulted in the dissipation of an additional 20 kcal excess energy in BATpos but not in BATneg individuals. The presence of BAT was associated with a unique systemic PUFA and oxylipin profile characterized by increased levels of anti-inflammatory omega-3 fatty acids as well as cytochrome P450 products but decreased concentrations of some proinflammatory hydroxyeicosatetraenoic acids when compared with BATneg individuals. Notably, cold exposure raised circulating levels of various lipids, including the recently identified BAT-derived circulating factors (BATokines) DiHOME and 12-HEPE, only in BATpos individuals. CONCLUSIONS: In summary, our data emphasize that BAT in humans is a major contributor toward cold-mediated energy dissipation and a critical organ in the regulation of the systemic lipid pool.

Thrombospondin-4 increases with the severity of peripheral arterial disease and is associated with diabetes.

Thrombospondin-4 (TSP-4) is an extracellular matrix protein of the vessel wall. Despite bench evidence, its significance in the clinical setting of atherosclerosis is missing. TSP-4 (ng/ml) was measured in 365 PAD patientsusing a commercially available ELISA. PAD was diagnosed by the ankle-brachial index (ABI) and clinically graded using the Fontaine classification. TSP-4 levels were significantly higher in Fontaine II vs. Fontaine I (4.78 ± 0. 42, 4.69 ± 0.42, p = 0.043). TSP-4 significantly correlated with ABI (r = - 0.141, p = 0.023, n = 259) after the exclusion of mediasclerotic patients. Binary logistic regression analysis for Fontaine I vs. II showed an OR of 1.70 (1.02-2.82) in a multivariable model adjusted for traditional risk factors. Interestingly, TSP-4 levels were higher in patients with type 2 diabetes mellitus or prediabetes (DGT) compared with normal glucose tolerance (NGT) (4.76 ± 0.42 vs. 4.66 ± 0.41, p = 0.035). ANOVA for PAD and diabetes subgroups showed a linear increase with disease burden with the highest difference between Fontaine I-NGT and Fontaine II-DGT (4.59 ± 0.40, 4.79 ± 0.43, p = 0.015). TSP-4 levels increased with PAD severity and showed a former unknown association with diabetes. Thus, TSP-4 could be a novel marker of atherosclerotic activity, especially in the major subgroup of patients with concomitant diabetes.

Adipose tissue browning in mice and humans

In the midst of an obesity epidemic, the promotion of brown adipose tissue (BAT) function and the browning of white adipose tissue (WAT) have emerged as promising therapeutic targets to increase energy expenditure and counteract weight gain. Despite the fact that the thermogenic potential of bone fide BAT in rodents is several orders of magnitudes higher than white fat containing brite/beige adipocytes, WAT browning represents a particularly intriguing concept in humans given the extreme amount of excess WAT in obese individuals. In addition, the clear distinction between classic brown and beige fat that has been proposed in mice does not exist in humans. In fact, studies of human BAT biopsies found controversial results suggesting both classic brown and beige characteristics. Irrespective of the true 'color', accumulating evidence suggests the induction of thermogenic adipocytes in human WAT depots in response to specific stimuli, highlighting that WAT browning may occur in both, mice and humans. These observations also emphasize the great plasticity of human fat depots and raise important questions about the metabolic properties of thermogenically active adipose tissue in humans and the potential therapeutic implications. We will first review the cellular and molecular aspects of selected adipose tissue browning concepts that have been identified in mouse models with emphasis on neuronal factors, the microbiome, immune cells and several hormones. We will also summarize the evidence for adipose tissue browning in humans including some experimental pharmacologic approaches.