RESUMEN
The voltage-gated hydrogen channel Hv1 encoded in humans by the HVCN1 gene is a highly selective proton channel that allows large fluxes of protons across biological membranes. Hv1 form functional dimers of four transmembrane spanning proteins resembling the voltage sensing domain of potassium channels. Each subunit is highly selective for protons and is controlled by changes in the transmembrane voltage and pH gradient. Hv1 is most expressed in phagocytic cells where it sustains NADPH oxidase-dependent bactericidal function and was reported to facilitate antibody production by B cells and to promote the maturation and motility of spermatocytes. Hv1 contributes to neuroinflammation following brain damage and favors cancer progression possibly by extruding protons generated during aerobic glycolysis of cancer cells. Lack of specific Hv1 inhibitors has hampered translation of this knowledge to treat immune, fertility, or malignancy diseases. In this study, we show that the genetic deletion of Hv1 delays tumor development in a mouse model of granulocytic sarcoma and report the discovery and characterization of two novel bioavailable inhibitors of Hv1 channels that we validate by orthogonal assays and electrophysiological recordings.
Asunto(s)
Canales Iónicos , Protones , Animales , Humanos , Masculino , Ratones , Membrana Celular/metabolismo , Canales Iónicos/genética , Canales Iónicos/metabolismo , NADPH Oxidasas/metabolismo , Fagocitos/metabolismoRESUMEN
Not all antibodies against SARS-CoV-2 inhibit viral entry, and hence, infection. Neutralizing antibodies are more likely to reflect real immunity; however, certain tests investigate protein/protein interaction rather than the fusion event. Viral and pseudoviral entry assays detect functionally active antibodies but are limited by biosafety and standardization issues. We have developed a Spike/ACE2-dependent fusion assay, based on a split luciferase. Hela cells stably transduced with Spike and a large fragment of luciferase were co-cultured with Hela cells transduced with ACE2 and the complementary small fragment of luciferase. Cell fusion occurred rapidly allowing the measurement of luminescence. Light emission was abolished in the absence of Spike and reduced in the presence of proteases. Sera from COVID-19-negative, non-vaccinated individuals or from patients at the moment of first symptoms did not lead to a significant reduction of fusion. Sera from COVID-19-positive patients as well as from vaccinated individuals reduced the fusion. This assay was more correlated to pseudotyped-based entry assay rather than serology or competitive ELISA. In conclusion, we report a new method measuring fusion-inhibitory antibodies in serum, combining the advantage of a complete Spike/ACE2 interaction active on entry with a high degree of standardization, easily allowing automation in a standard bio-safety environment.
Asunto(s)
COVID-19 , Humanos , COVID-19/prevención & control , Enzima Convertidora de Angiotensina 2 , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Células HeLa , Anticuerpos Antivirales , Peptidil-Dipeptidasa A , Anticuerpos Neutralizantes , VacunaciónRESUMEN
Background: The SARS-CoV-2 pandemic was particularly devastating for elderly people, and the underlying mechanisms of the disease are still poorly understood. In this study, we investigated fusion inhibitory antibodies (fiAbs) in elderly and younger COVID-19 patients and analyzed predictive factors for their occurrence. Methods: Data and samples were collected in two cohorts of hospitalized patients. A fusion assay of SARS-CoV-2 spike-expressing cells with ACE2-expressing cells was used to quantify fiAbs in the serum of patients. Results: A total of 108 patients (52 elderly (mean age 85 ± 7 years); 56 young (mean age 52 ± 10 years)) were studied. The concentrations of fiAbs were lower in geriatric patients, as evidenced at high serum dilutions (1/512). The association between fiAbs and anti-Spike Ig levels was weak (correlation coefficient < 0.3), but statistically significant. Variables associated with fusion were the delay between the onset of symptoms and testing (HR = −2.69; p < 0.001), clinical frailty scale (HR = 4.71; p = 0.035), and WHO severity score (HR = −6.01, p = 0.048). Conclusions: Elderly patients had lower fiAbs levels after COVID-19 infection. The decreased fiAbs levels were associated with frailty.
RESUMEN
Phenazopyridine is a widely used drug against urinary tract pain. The compound has also been shown to enhance neural differentiation of pluripotent stem cells. However, its mechanism of action is not understood. Based on its chemical structure, we hypothesized that phenazopyridine could be a kinase inhibitor. Phenazopyridine was investigated in the following experimental systems: 1) activity of kinases in pluripotent stem cells; 2) binding to recombinant kinases, and 3) functional impact on pluripotent stem cells. Upon addition to pluripotent stem cells, phenazopyridine induced changes in kinase activities, particularly involving Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinases, and AKT pathway kinases. To identify the primary targets of phenazopyridine, we screened its interactions with 401 human kinases. Dose-inhibition curves showed that three of these kinases interacted with phenazopyridine with sub-micromolar binding affinities: cyclin-G-associated kinase, and the two phosphatidylinositol kinases PI4KB and PIP4K2C, the latter being known for participating in pain induction. Docking revealed that phenazopyridine forms strong H-bonds with the hinge region of the ATP-binding pocket of these kinases. As previous studies suggested increased autophagy upon inhibition of the phosphatidyl-inositol/AKT pathway, we also investigated the impact of phenazopyridine on this pathway and found an upregulation. In conclusion, our study demonstrates for the first time that phenazopyridine is a kinase inhibitor, impacting notably phosphatidylinositol kinases involved in nociception.
RESUMEN
Exogenous oxytocin administration in obese mice, rats, and monkeys was shown to induce sustained weight loss, mostly due to a decrease in fat mass, accompanied by an improvement of glucose metabolism. A pilot study in obese humans confirmed the weight-reducing effect of oxytocin. Knowledge about circulating oxytocin levels in human obesity might help indicating which obese subjects could potentially benefit from an oxytocin treatment. Conclusive results on this topic are missing. The aim of this study was to measure circulating oxytocin levels in lean (n = 37) and obese (n = 72) individuals across a wide range of body mass index (BMI) values (18.5-60 kg/m2) and to determine the impact of pronounced body weight loss following gastric bypass surgery in 12 morbidly obese patients. We observed that oxytocin levels were unchanged in overweight and in class I and II obese subjects and only morbidly obese patients (obesity class III, BMI > 40 kg/m2) exhibited significantly higher levels than lean individuals, with no modification 1 year after gastric bypass surgery, despite substantial body weight loss. In conclusion, morbidly obese subjects present elevated oxytocin levels which were unaltered following pronounced weight loss.
Asunto(s)
Derivación Gástrica/estadística & datos numéricos , Obesidad Mórbida/metabolismo , Oxitocina/metabolismo , Pérdida de Peso/fisiología , Adiposidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/fisiopatología , Obesidad Mórbida/cirugía , Oxitocina/uso terapéutico , Proyectos Piloto , Resultado del TratamientoRESUMEN
Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 µg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin.
Asunto(s)
Dieta Alta en Grasa , Ingestión de Alimentos/efectos de los fármacos , Leptina/farmacología , Obesidad/etiología , Oxitocina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones ObesosRESUMEN
BACKGROUND: Oleoylethanolamide (OEA) is an endocannabinoid that controls food intake, energy expenditure and locomotor activity. Its anorexigenic effect appears to be mediated by PPARα, but the tissue where the presence of this receptor is required for OEA to inhibit feeding is unknown as yet. Previous studies point to a possible role of proximal enterocytes and neurons of the nodose ganglion. MATERIALS AND METHODS: Acute intraperitoneal OEA effects on food intake, energy expenditure, respiratory exchange ratio (RER) and locomotor activity were studied in control mice (PPARα-loxP) and intestinal (Villin-Cre;PPARα-loxP) or nodose ganglion (Phox2B-Cre;PPARα-loxP) specific PPARα knockout mice placed in calorimetric cages. RESULTS: OEA administration to both intestinal and nodose ganglion PPARα knockout mice decreased food intake, RER (leading to increased lipid oxidation) and locomotor activity as in control mice. However, while OEA injection acutely decreased energy expenditure in controls, this effect was not observed in mice devoid of PPARα in the intestine. CONCLUSION: These results indicate that the OEA effect on food intake is independent from the presence of PPARα in the intestine and the nodose ganglion, while the impact of OEA on energy expenditure requires the presence of PPARα in the intestine.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Endocannabinoides/farmacología , Metabolismo Energético/efectos de los fármacos , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Ganglio Nudoso/metabolismo , Ácidos Oléicos/farmacología , PPAR alfa/metabolismo , Animales , Mucosa Intestinal/efectos de los fármacos , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Ganglio Nudoso/efectos de los fármacos , PPAR alfa/efectos de los fármacos , PPAR alfa/genéticaRESUMEN
Brown adipose tissue (BAT), characterized by the presence of uncoupling protein 1 (UCP1), has been described as metabolically active in humans. Lou/C rats, originating from the Wistar strain, are resistant to obesity. We previously demonstrated that Lou/C animals express UCP1 in beige adipocytes in inguinal white adipose tissue (iWAT), suggesting a role of this protein in processes such as the control of body weight and the observed improved insulin sensitivity. A ß3 adrenergic agonist was administered for 2 weeks in Wistar and Lou/C rats to activate UCP1 and delineate its metabolic impact. The treatment brought about decreases in fat mass and improvements in insulin sensitivity in both groups. In BAT, UCP1 expression increased similarly in response to the treatment in the two groups. However, the intervention induced the appearance of beige cells in iWAT, associated with a marked increase in UCP1 expression, in Lou/C rats only. This increase was correlated with a markedly enhanced glucose uptake measured during euglycemic-hyperinsulinemic clamps, suggesting a role of beige cells in this process. Activation of UCP1 in ectopic tissues, such as beige cells in iWAT, may be an interesting therapeutic approach to prevent body weight gain, decrease fat mass, and improve insulin sensitivity.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Resistencia a la Insulina/fisiología , Canales Iónicos/metabolismo , Proteínas Mitocondriales/metabolismo , Obesidad/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Composición Corporal/efectos de los fármacos , Composición Corporal/fisiología , Dioxoles/farmacología , Canales Iónicos/genética , Masculino , Proteínas Mitocondriales/genética , Obesidad/genética , Ratas , Ratas Wistar , Termogénesis/efectos de los fármacos , Termogénesis/fisiología , Proteína Desacopladora 1RESUMEN
BACKGROUND & AIMS: PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases. METHODS: Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo. RESULTS: PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice. CONCLUSIONS: Although steatosis develops in LPTEN KO mice, PTEN deficiency in hepatocytes promotes a crosstalk between liver and muscle, as well as adipose tissue, resulting in enhanced insulin sensitivity, improved glucose tolerance and decreased adiposity.
Asunto(s)
Adiposidad/genética , Hígado Graso/genética , Regulación de la Expresión Génica , Resistencia a la Insulina , Lipogénesis/genética , Fosfohidrolasa PTEN/genética , ARN/genética , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Western Blotting , Células Cultivadas , Hígado Graso/diagnóstico , Hígado Graso/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Metabolismo de los Lípidos , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Fosfohidrolasa PTEN/deficiencia , Fenotipo , Tomografía Computarizada por Rayos XRESUMEN
Oxytocin has been suggested as a novel therapeutic against obesity, because it induces weight loss and improves glucose tolerance in diet-induced obese rodents. A recent clinical pilot study confirmed the oxytocin-induced weight-reducing effect in obese nondiabetic subjects. Nevertheless, the mechanisms involved and the impact on the main comorbidity associated with obesity, type 2 diabetes, are unknown. Lean and ob/ob mice (model of obesity, hyperinsulinemia, and diabetes) were treated for 2 weeks with different doses of oxytocin, analogues with longer half-life (carbetocin) or higher oxytocin receptor specificity ([Thr4,Gly7]-oxytocin). Food and water intake, body weight, and glycemia were measured daily. Glucose, insulin, and pyruvate tolerance, body composition, several hormones, metabolites, gene expression, as well as enzyme activities were determined. Although no effect of oxytocin on the main parameters was observed in lean mice, the treatment dose-dependently reduced food intake and body weight gain in ob/ob animals. Carbetocin behaved similarly to oxytocin, whereas [Thr4,Gly7]-oxytocin (TGOT) and a low oxytocin dose decreased body weight gain without affecting food intake. The body weight gain-reducing effect was limited to the fat mass only, with decreased lipid uptake, lipogenesis, and inflammation, combined with increased futile cycling in abdominal adipose tissue. Surprisingly, oxytocin treatment of ob/ob mice was accompanied by a worsening of basal glycemia and glucose tolerance, likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These results impose careful selection of the conditions in which oxytocin treatment should be beneficial for obesity and its comorbidities, and their relevance for human pathology needs to be determined.
Asunto(s)
Adiposidad/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Oxitocina/uso terapéutico , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Glucosa/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/complicaciones , Obesidad/metabolismo , Oxitocina/administración & dosificación , Delgadez/metabolismo , Delgadez/patologíaRESUMEN
The Lou/C rat, an inbred strain of Wistar origin, was described as a model of resistance to age- and diet-induced obesity. Although such a resistance involves many metabolic parameters described in our previous studies, Lou/C rats also exhibit a spontaneous food restriction due to decreased food consumption during the nocturnal period. We then attempted to delineate the leptin sensitivity and mechanisms implicated in this strain, using different protocols of acute central and peripheral leptin administration. A first analysis of the meal patterns revealed that Lou/C rats eat smaller meals, without any change in meal number compared to age-matched Wistar animals. Although the expression of the recognized leptin transporters (leptin receptors and megalin) measured in the choroid plexus was normal in Lou/C rats, the decreased triglyceridemia observed in these animals is compatible with an increased leptin transport across the blood brain barrier. Improved hypothalamic leptin signaling in Lou/C rats was also suggested by the higher pSTAT3/STAT3 (signal transducer and activator of transcription 3) ratio observed following acute peripheral leptin administration, as well as by the lower hypothalamic mRNA expression of the suppressor of cytokine signaling 3 (SOCS3), known to downregulate leptin signaling. To conclude, spontaneous hypophagia of Lou/C rats appears to be related to improved leptin sensitivity. The main mechanism underlying such a phenomenon consists in improved leptin signaling through the Ob-Rb leptin receptor isoform, which seems to consequently lead to overexpression of brain-derived neurotrophic factor (BDNF) and thyrotropin-releasing hormone (TRH).
Asunto(s)
Ingestión de Alimentos , Leptina/metabolismo , Obesidad/metabolismo , Animales , Hipotálamo/metabolismo , Masculino , Obesidad/genética , Obesidad/fisiopatología , ARN Mensajero/genética , Ratas , Ratas Wistar , Receptores de Leptina/metabolismo , Transducción de Señal , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
Glucocorticoids (GCs) are involved in multiple metabolic processes, including the regulation of insulin sensitivity and adipogenesis. Their action partly depends on their intracellular activation by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). We previously demonstrated that central GC administration promotes hyperphagia, body weight gain, hyperinsulinemia and marked insulin resistance at the level of skeletal muscles. Similar dysfunctions have been reported to occur upon specific overexpression of 11ß-HSD1 in adipose tissue. The aim of the present study was therefore to determine whether the effects of central GC infusion may enhance local GC activation in white adipose tissue. Male Wistar and Sprague Dawley (SD) rats were intracerebroventricularly infused with GCs for 2 to 3 days. Body weight, food intake and metabolic parameters were measured, and expression of enzymes regulating 11ß-HSD1, as well as that of genes regulated by GCs, were quantified. Central GC administration induced a significant increase in body weight gain and in 11ß-HSD1 and resistin expression in adipose tissue. A decrease 11ß-HSD1 expression was noticed in the liver of SD rats, as a partial compensatory mechanism. Such effects of GCs are centrally elicited. This model of icv dexamethasone infusion thus appears to be a valuable acute model, that helps delineating the initial metabolic defects occurring in obesity. An impaired downregulation of intracellular GC activation in adipose tissue may be important for the development of insulin resistance.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/enzimología , Expresión Génica/efectos de los fármacos , Glucocorticoides/administración & dosificación , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Dexametasona/administración & dosificación , Infusiones Intraventriculares , Infusiones Subcutáneas , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid ß-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid ß-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.
Asunto(s)
Fármacos Antiobesidad/farmacología , Dieta/efectos adversos , Obesidad/tratamiento farmacológico , Obesidad/etiología , Oxitocina/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/sangre , Fármacos Antiobesidad/metabolismo , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Endocannabinoides , Técnicas de Inactivación de Genes , Resistencia a la Insulina , Masculino , Ratones , Obesidad/metabolismo , Obesidad/fisiopatología , Ácidos Oléicos/biosíntesis , Ácidos Oléicos/metabolismo , Oxitocina/administración & dosificación , Oxitocina/biosíntesis , Oxitocina/sangre , PPAR alfa/deficiencia , PPAR alfa/genética , PPAR alfa/metabolismo , RatasRESUMEN
Recent studies describe the Lou/C rat as a model of resistance to age- and diet-induced obesity and suggest a preferential channeling of nutrients toward utilization rather than storage under standard feeding conditions. The purpose of the present study was to evaluate lipid metabolism of Lou/C and Wistar rats under a high-fat (HF) diet. Four-month-old male Lou/C and Wistar animals were submitted to a 40% HF diet for 5-9 wk. Evolution of food intake, body weight, and body composition, hormonal parameters, and expression of key transcription factors and enzymes involved in lipid metabolism were determined. Wistar rats developed obesity after 5 wk of HF diet, as previously described. Among the various parameters measured, accumulation of intraperitoneal fat was particularly evident in HF-fed Wistar rats. In these animals, thermogenesis was, however, stimulated as a likely compensatory mechanism against the development of obesity. On the contrary, Lou/C animals failed to develop obesity under such a diet, and intraperitoneal fat, not including epididymal and retroperitoneal fat depots, was virtually absent. Enzyme measurements confirmed lipid utilization rather than storage, which was accompanied by the striking emergence of uncoupling protein-1, characteristic of brown adipocytes, in white adipose tissue, particularly in the subcutaneous depot.