Thermogenic Response Research Articles

Levels of β-klotho determine the thermogenic responsiveness of adipose tissues: involvement of the autocrine action of FGF21.

Fibroblast growth factor-21 (FGF21) is a hormonal regulator of metabolism; it promotes glucose oxidation and the thermogenic capacity of adipose tissues. The levels of β-klotho (KLB), the co-receptor required for FGF21 action, are decreased in brown (BAT) and white (WAT) adipose tissues during obesity, diabetes, and lipodystrophy. Reduced β-klotho levels have been proposed to account for FGF21 resistance in these conditions. In this study, we explored whether downregulation of β-klotho affects metabolic regulation and the thermogenic responsiveness of adipose tissues using mice with total (KLB-KO) or partial (KLB-heterozygotes) ablation of β-klotho. We herein show that KLB gene dosage was inversely associated with adiposity in mice. Upon cold exposure, impaired browning of subcutaneous WAT and milder alterations in BAT were associated with reduced KLB gene dosage in mice. Cultured brown and beige adipocytes from mice with total or partial ablation of the KLB gene showed reduced thermogenic responsiveness to β3-adrenergic activation by treatment with CL316,243, indicating that these effects were cell-autonomous. Deficiency in FGF21 mimicked the KLB-reduction-induced impairment of thermogenic responsiveness in brown and beige adipocytes. These results indicate that the levels of KLB in adipose tissues determine their thermogenic capacity to respond to cold and/or adrenergic stimuli. Moreover, an autocrine action of FGF21 in brown and beige adipocytes may account for the ability of the KLB level to influence thermogenic responsiveness.NEW & NOTEWORTHY Reduced levels of KLB (the obligatory FGF21 co-receptor), as occurring in obesity and type 2 diabetes, reduce the thermogenic responsiveness of adipose tissues in cold-exposed mice. Impaired response to β3-adrenergic activation in brown and beige adipocytes with reduced KLB occurs in a cell-autonomous manner involving an autocrine action of FGF21.

Social interaction and the thermogenic response of chicken hatchlings

The aggregation of two or more individuals of the same species (huddling) is common in mammals and birds, especially in the cold. The physical contact reduces the weight-specific body surface exposed to the environment, thus lowering heat loss and the thermogenic needs. This study investigated the possibility that the mere presence of a conspecific, in absence of physical contact, may by itself influence metabolic rate during cold. The oxygen consumption (Vo2) of pairs of chicken hatchlings was measured when the hatchlings were in isolation (individuals), together in the respirometer but kept separated by a grid (separated) or together in the respirometer free to huddle (together), in random order, in warm (ambient normothermia, 37.5 °C) and cold conditions (26 °C, 1 h). In warm, Vo2 did not differ significantly among individuals, separated and together (~ 1.03 ± 0.04 ml O2/min). During the whole cold period, Vo2 of individuals exceeded the value by 23.3 ± 3.1 ml of O2, significantly more than in separated (15.3 ± 2.0 ml O2, P<0.01) and together (13.9 ± 3.3 ml O2; P<0.001). Separated and together did not differ significantly. Vo2 in the cold averaged 149 ± 7% of the value measured in normothermia in isolated, 132 ± 5% in separated and 128 ± 7% in together. By the end of the cold-exposure, Vo2 averaged 166 ± 8% of normothermia in isolated, 146 ± 8% in separated and 140 ± 9% in together. In all cases, values of isolated significantly exceeded those of separated (P<0.01) and together (P<0.0001), while separated and together did not differ from each other (P>0.05; Two-way RM ANOVA). Hence, in this experimental model, social interaction without physical contact decreased the thermogenic response to cold as much as huddling did. Presumably, during the cold exposure, social interaction lowered the additional energetic cost of the stress of isolation.

The Rosmarinus Bioactive Compound Carnosic Acid Is a Novel PPAR Antagonist That Inhibits the Browning of White Adipocytes.

Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to control fat mass such as in obesity or cachexia. The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function. We used human multipotent adipose-derived stem (hMADS) cells differentiated into white or brite adipocytes. The expression of key marker genes was determined using RT-qPCR and western blotting. We show here that CA inhibits the browning of white adipocytes and favors decreased gene expression of thermogenic markers. CA treatment does not affect β-adrenergic response. Importantly, the effects of CA are fully reversible. We used transactivation assays to show that CA has a PPARα/γ antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.

The crucial roles of coagulation factors in inducing brown adipose tissue dysfunction and systemic metabolic disorder in obesity

Abstract The prevalence of obesity is increasing worldwide. Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Analyzing deposited microarray data, we found transcripts for coagulation factors including factor VII (F7), factor X (F10), and PAR1 receptor were increased in BAT from obese mice. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. Fxa inhibition reduced reactive oxygen species (ROS) level in BAT. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. We generated BAT specific PAR1 KO mice. BAT-PAR1 KO mice exhibited re-browning of BAT along with reduced ROS level in this tissue. In BAT-PAR1 KO mice, glucose intolerance and thermogenic response under a metabolically stressed condition were ameliorated. In differentiated brown adipocytes, FXa markedly increased mitochondrial ROS and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes. Funding Acknowledgement Type of funding source: None

Median preoptic area neurons are required for the cooling and febrile activations of brown adipose tissue thermogenesis in rat

Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. We employed neuroanatomical and in vivo electrophysiological techniques to identify a source of excitation to thermogenesis-promoting neurons in the DMH that is required for cold defense and fever. Inhibition of median preoptic area (MnPO) neurons blocked the BAT thermogenic responses during both PGE2-induced fever and cold exposure. Disinhibition or direct activation of MnPO neurons induced a BAT thermogenic response in warm rats. Blockade of ionotropic glutamate receptors in the DMH, or brain transection rostral to DMH, blocked cold-evoked or NMDA in MnPO-evoked BAT thermogenesis. RNAscope technique identified a glutamatergic population of MnPO neurons that projects to the DMH and expresses c-Fos following cold exposure. These discoveries relative to the glutamatergic drive to BAT sympathoexcitatory neurons in DMH augment our understanding of the central thermoregulatory circuitry in non-torpid mammals. Our data will contribute to the development of novel therapeutic approaches to induce therapeutic hypothermia for treating drug-resistant fever, and for improving glucose and energy homeostasis.

Insulin sensing by astrocytes is critical for normal thermogenesis and body temperature regulation.

The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

CD38 downregulation modulates NAD+ and NADP(H) levels in thermogenic adipose tissues

Different strategies to boost NAD+ levels are considered promising means to promote healthy aging and ameliorate dysfunctional metabolism. CD38 is a NAD+-dependent enzyme involved in the regulation of different cell functions. In the context of systemic energy metabolism, it has been demonstrated that brown adipocytes, the parenchymal cells of brown adipose tissue (BAT) as well as beige adipocytes that emerge in white adipose tissue (WAT) depots in response to catabolic conditions, are important to maintain metabolic homeostasis. In this study we aim to understand the functional relevance of CD38 for NAD+ and energy metabolism in BAT and WAT, also using a CD38−/− mouse model.During cold exposure, an increase in NAD+ levels occurred in BAT of wild type mice, together with a marked downregulation of CD38, as detected at the mRNA and protein level. CD38 downregulation was observed also in WAT of cold-exposed mice, where it was accompanied by a strong increase in NADP(H) levels. Accordingly, NAD kinase and glucose-6-phosphate dehydrogenase activities were enhanced in WAT (but not in BAT). Increased NAD+ levels were observed in BAT/WAT from CD38−/− compared with wild type mice, in line with CD38 being a major NAD+-consumer in AT. CD38−/− mice kept at 6 °C had higher levels of Ucp1 and Pgc-1α in BAT and WAT, and increased levels of phosphorylated hormone-sensitive lipase in BAT, compared with wild type mice.These results demonstrate that CD38, by modulating cellular NAD(P)+ levels, is involved in the regulation of thermogenic responses in cold-activated BAT and WAT.

Thermogenic responses in Eurasian Tree Sparrow (Passer montanus) to seasonal acclimatization and temperature-photoperiod acclimation

BackgroundSmall birds in temperate habitats must either migrate, or adjust aspects of their morphology, physiology and behavior to cope with seasonal change in temperature and photoperiod. It is, however, difficult to accurately measure how seasonal changes in temperature and photoperiod affect physiological processes such as basal metabolic rate (BMR) and metabolic activity. To address this problem, we collected data in each month of the year on body mass (Mb) and BMR, and conducted a series of experiments to determine the effect of temperature and photoperiod on Mb, BMR and physiological markers of metabolic activity, in the Eurasian Tree Sparrow (Passer montanus).MethodsIn one experiment, we measured monthly change in Mb and BMR in a captive group of birds over a year. In another experiment, we examined the effects of acclimating birds to two different temperatures, 10 and 30 °C, and a long and a short photoperiod (16 h light:8 h dark and 8 h light:16 h dark, respectively) for 4 weeks.ResultsWe found that these treatments induced sparrows to adjust their Mb and metabolic rate processes. Acclimation to 30 °C for 4 weeks significantly decreased sparrows’ Mb, BMR, and energy intake, including both gross energy intake and digestible energy intake, compared to birds acclimated to 10 °C. The dry mass of the liver, kidneys and digestive tract of birds acclimated to 30 °C also significantly decreased, although their heart and skeletal muscle mass did not change significantly relative to those acclimated to 10 °C. Birds acclimated to 30 °C also had lower mitochondrial state-4 respiration (S4R) and cytochrome c oxidase (COX) activity in their liver and skeletal muscle, compared to those acclimated to 10 °C. Birds acclimated to the long photoperiod also had lower mitochondrial S4R and COX activity in their liver, compared to those acclimated to the short photoperiod.ConclusionsThese results illustrate the changes in morphology, physiology, and enzyme activity induced by seasonal change in temperature and photoperiod in a small temperate passerine. Both temperature and photoperiod probably have a strong effect on seasonal variation in metabolic heat production in small birds in temperate regions. The effect of temperature is, however, stronger than that of photoperiod.

Real-time nanodiamond thermometry probing in vivo thermogenic responses.

Real-time temperature monitoring inside living organisms provides a direct measure of their biological activities. However, it is challenging to reduce the size of biocompatible thermometers down to submicrometers, despite their potential applications for the thermal imaging of subtissue structures with single-cell resolution. Here, using quantum nanothermometers based on optically accessible electron spins in nanodiamonds, we demonstrate in vivo real-time temperature monitoring inside Caenorhabditis elegans worms. We developed a microscope system that integrates a quick-docking sample chamber, particle tracking, and an error correction filter for temperature monitoring of mobile nanodiamonds inside live adult worms with a precision of ±0.22°C. With this system, we determined temperature increases based on the worms' thermogenic responses during the chemical stimuli of mitochondrial uncouplers. Our technique demonstrates the submicrometer localization of temperature information in living animals and direct identification of their pharmacological thermogenesis, which may allow for quantification of their biological activities based on temperature.

Effect of sex and sex steroids on brown adipose tissue heat production in humans

Retrospective studies suggest that women have more active brown adipose tissue (BAT) than men, but little is known of the effect of fluctuating sex steroids across the menstrual cycle on thermogenesis in women. To characterise the effects of sex and sex steroids on BAT activity we recruited healthy weight men (n = 14) and women at two stages of the menstrual cycle (luteal, n = 9; follicular, n = 11). Infrared thermography measured supraclavicular temperature to index BAT thermogenesis in response to both cold (immersion of one hand in water at 15°C) and meal (Ensure, 10 kcal/kg body weight) stimuli. Adaptive BAT temperature responses were greater (P < 0.05) in women than men, irrespective of stage of menstrual cycle. Whereas during cold exposure, the increase in BAT temperature was abrogated (P < 0.05) in women during follicular phase compared to men and women during luteal phase. Plasma concentrations of progesterone, 17β-estradiol, testosterone and cortisol were measured. Regression analyses demonstrated that baseline BAT temperature was positively correlated (P < 0.05) with progesterone levels, but was inversely associated (P < 0.05) with cortisol concentration. Both cold- and meal-induced changes in BAT temperature mildly correlated (P = 0.07; P < 0.05) with 17β-estradiol levels, but not with testosterone concentrations. Baseline supraclavicular temperature is elevated in women during the luteal phase of the menstrual cycle, which correlated with elevated progesterone concentrations. Women exhibited greater thermogenic responses than men, irrespective of the state of the menstrual cycle, which was associated with plasma levels of 17β-estradiol. We conclude that sex steroids may regulate BAT thermogenesis in healthy adults.

A Gluten-Free Meal Produces a Lower Postprandial Thermogenic Response Compared to an Iso-Energetic/Macronutrient Whole Food or Processed Food Meal in Young Women: A Single-Blind Randomized Cross-Over Trial.

Consumption of ultra-processed food (PF) is associated with obesity risk compared with whole food (WF) intake. Less is known regarding the intake of gluten-free (GF) food products. The purpose of this study was to directly compare the thermic effect (TEM), substrate utilization, hunger/taste ratings, and glucose response of three different meals containing PF, WF, and GF food products in young healthy women. Eleven volunteers completed all three iso-caloric/macronutrient test meals in a single-blind, randomized crossover design: (1) whole food meal (WF); (2) processed food meal (PF); or (3) gluten-free meal (GF). TEM was significantly lower following GF compared with WF (−20.94 kcal/meal, [95% CI, −35.92 to −5.96], p = 0.008) and PF (mean difference: −14.94 kcal/meal, [95% CI, −29.92 to 0.04], p = 0.04), respectively. WF consumption resulted in significantly higher feelings of fullness compared to GF (mean difference: +14.36%, [95% CI, 3.41 to 25.32%], p = 0.011) and PF (mean difference: +16.81%, [95% CI, 5.62 to 28.01%], p = 0.004), respectively, and enhanced palatability (taste of meal) compared to PF meal (mean Δ: +27.41%, [95% CI, 5.53 to 49.30%], p = 0.048). No differences existed for substrate utilization and blood glucose response among trials. Consumption of a GF meal lowers postprandial thermogenesis compared to WF and PF meals and fullness ratings compared to a WF meal which may impact weight control and obesity risk over the long-term.

Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity.

Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide (Agrp) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in Agrp neuron biology, possibly secondary to altered CREB signaling.

209-OR: Evidence that Agrp Neuron Activation Drives Cold-Induced Hyperphagia

Although hyperphagic feeding during cold exposure is widely viewed as a response to the negative energy state that results from increased thermogenesis, the underlying mechanisms are unknown. We investigated an alternative hypothesis, that during cold exposure, hyperphagia is mounted in anticipation of homeostatic need, rather than as a compensatory response. In support of this hypothesis, we report that in chow-fed mice acutely housed at 14°C, increases of food intake and thermogenesis occur both rapidly and simultaneously, implying hyperphagia is not mounted as a compensatory response. We next asked whether this cold-induced feeding response involves activation of agouti-related peptide (Agrp) neurons, which are implicated in other forms of hyperphagic feeding. Consistent with this hypothesis, we report that Agrp neurons are activated within 1-2 min of cold exposure and prior to the onset of hyperphagia, as judged by in vivo fiber photometry and confirmed by cFos induction (Agrp+/cFos+, 22°C: 5.3±4.5% vs. 14°C: 20.2±6.1%; p&amp;lt;0.01). To test whether Agrp neuron activation is required for cold-induced hyperphagia, we employed a chemogenetic strategy to silence Agrp neurons. As predicted, their silencing prevented hyperphagic feeding (2h food intake after housing at 14°C: 0.26±0.06 g vs. 0.10±0.04 g; p&amp;lt;0.05), but not the associated thermogenic response (0.63 vs. 0.62 kcal/hr; p=ns) during cold exposure. Interestingly, cold-induced hyperphagia is absent in mice with diet-induced obesity (DIO). Consequently, unlike chow-fed mice, these animals lose weight during cold exposure. These observations suggest that 1) Agrp neurons lie downstream of thermoregulatory neurocircuits, 2) during cold exposure, increased Agrp neuronal firing occurs rapidly as part of a homeostatic response that preserves body temperature and energy stores, and 3) this response appears to be impaired in mice with DIO. Future studies will map the neurocircuitry underlying these responses and clarify how DIO impairs their activation. Disclosure J.D. Deem: None. C.L. Faber: None. C. Pedersen: None. B.N. Phan: None. K. Ogimoto: None. S.A. Larsen: None. M.A. Tran: None. V. Damian: None. K. Kaiyala: None. J. Scarlett: None. M.R. Bruchas: None. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. G.J. Morton: Research Support; Self; Novo Nordisk A/S. Funding American Diabetes Association (1-19-PDF-103 to J.D.D.); Dick and Julia McAbee Foundation; National Institutes of Health (T32-HL007028-39, R01DK089056, R01DK101997, R01DK124238, R01DK089056, P30DK017047, P30DK035816)

SAT-LB107 Insulin Sensing by Astrocytes Is Critical for Normal Thermogenesis and Body Temperature Regulation

The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed a significant decrease in energy expenditure and a striking decrease in basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. Brown adipose tissue in IRKOGFAP mice exhibited increased adipocyte size, more apoptosis, loss of innervation, and decreased βAR3 expression levels. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

Metabolic Responses to 24-Hour Fasting and Mild Cold Exposure in Overweight Individuals Are Correlated and Accompanied by Changes in FGF21 Concentration.

A greater decrease in 24-h energy expenditure (24 EE) during 24-h fasting defines a "thriftier" metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24 EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24-h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male; aged 36.6 ± 11.4 years; percentage body fat 34.8 ± 10.5%). Greater decrease in 24 EE during fasting (thriftier phenotype) was associated with less increase in 24 EE during COLD (i.e., less cold-induced thermogenesis). Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24-h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated with and mediated by the liver-derived hormone FGF21. Thus, the 24 EE response to COLD further identifies the "thrifty" versus "spendthrift" phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change.

CNGA3 acts as a cold sensor in hypothalamic neurons.

Most mammals maintain their body temperature around 37°C, whereas in hibernators it can approach 0°C without triggering a thermogenic response. The remarkable plasticity of the thermoregulatory system allowed mammals to thrive in variable environmental conditions and occupy a wide range of geographical habitats, but the molecular basis of thermoregulation remains poorly understood. Here we leverage the thermoregulatory differences between mice and hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus) to investigate the mechanism of cold sensitivity in the preoptic area (POA) of the hypothalamus, a critical thermoregulatory region. We report that, in comparison to squirrels, mice have a larger proportion of cold-sensitive neurons in the POA. We further show that mouse cold-sensitive neurons express the cyclic nucleotide-gated ion channel CNGA3, and that mouse, but not squirrel, CNGA3 is potentiated by cold. Our data reveal CNGA3 as a hypothalamic cold sensor and a molecular marker to interrogate the neuronal circuitry underlying thermoregulation.

Non‐Contrast Ultrasound Perfusion Imaging of Human Brown Adipose Tissue

Brown adipose tissue (BAT) is a highly vascularized tissue that uptakes and oxidizes fatty acids from the circulation in response to a cold stimulus, resulting in thermogenesis. Tissue perfusion has been proposed as an approach to understand BAT metabolism, but current imaging techniques require invasive contrast or ionizing radiation. Power Doppler ultrasound imaging enables sensitive, high temporal resolution measures of the movement of blood as it perfuses a tissue without the need for contrast injections. The purpose of this study was to explore the utility of non‐contrast ultrasound perfusion imaging of human BAT during personalized cooling. Five healthy subjects [4 men; age: 31.8 ± 5.6 yrs.; body mass index: 22.5 ± 3.3 kg/m2; total body fat % (dual‐energy x‐ray absorptiometry scan): 22.9 ±7.0 %] underwent an individualized, perception‐based cooling protocol to stimulate BAT. Infrared thermography, a surrogate measure of BAT activity, and power Doppler ultrasound images were acquired over the right and left supraclavicular space, respectively, every five minutes in thermoneutrality (TN; duration: 15 min) and during cold exposure (CE) to the participant’s shiver threshold (duration: 58.3 ± 10.8 min; cooling dose: 319.7 ± 140.4 °C*min). Ultrasound images were post‐processed with a block‐wise, independent component analysis filter to analyze signal changes related to perfusion. BAT regions of interest were defined, and TN and CE conditions were compared as the mean ± standard deviation of the difference in the 95th percentile skin temperatures (infrared thermography) and the mean power Doppler signal (ultrasound). Supraclavicular skin temperature increased by 0.56 ± −0.21 °C (95% bootstrap confidence interval (CI): −0.57 to 1.72 °C), indicating a potential thermogenic response of BAT to individualized cooling (TN: 33.8 ± 1.1 °C vs. CE: 34.3 ± 0.9 °C). Similarly, the mean power Doppler signal increased by 11.6 ± 3.8 dB (95% CI: 3.2 to 19.4 dB) following cold exposure (TN: 46.8 ± 5.3 dB vs. CE: 58.3 ± 9.1 dB). These preliminary data demonstrate the feasibility of non‐contrast ultrasound perfusion imaging to detect the microvascular response of BAT to a cold stimulus in healthy adults. Power Doppler ultrasound imaging could prove useful when combined with existing noninvasive modalities (e.g. magnetic resonance imaging) to assess both the perfusion and metabolic substrate uptake response of BAT to potential obesity‐targeted therapies.Support or Funding InformationNIDDK/NIH R01‐DK‐105371, NCATS/NIH UL1‐TR000445

Gender Differences in the Response to Short-term Cold Exposure in Young Adults.

Cold exposure (CE) has been shown to enhance energy expenditure by activating brown adipose tissue thermogenesis and metabolism in humans. However, it remains to be elucidated if there are gender-specific differences in cold-induced thermogenesis and metabolism. To study the impact of mild CE on resting energy expenditure (REE) and metabolism in males compared with females. A cross-sectional study. 117 healthy young Caucasians participated in this study (58 males). Mean age was 25.1 ± 3.6 years and mean body mass index 22.3 ± 1.7 kg/m2. Participants underwent a short-term CE using water perfused mattresses to activate nonshivering thermogenesis. REE was assessed before and 2 hours after CE followed by blood sampling. Selected metabolites and hormones were measured. Skin temperatures were monitored at various sites throughout the experiment. Participants showed a significant increase in REE after CE (6.5%, P < .001). This increase did not differ between genders (P = .908). However, there were differences between males and females in changes of plasma glucose (-5.1% versus -7.4%, P = .024), leptin (-14.3% versus -30.1%, P < .001) and adiponectin (5.4% versus 12.8%, P = .018) after CE. We observed a significant decrease of the supraclavicular skin temperature in men (-0.3%, P = .034), but not in women (0.3%, P = .326)(P = .019 between genders). We did not observe a difference in the thermogenic response, measured as change of REE, to CE in women compared with men. However, we found that some metabolic and hormonal changes were more pronounced in women than in men suggesting a gender-specific response to cold.

A central master driver of psychosocial stress responses in the rat.

The mechanism by which psychological stress elicits various physiological responses is unknown. We discovered a central master neural pathway in rats that drives autonomic and behavioral stress responses by connecting the corticolimbic stress circuits to the hypothalamus. Psychosocial stress signals from emotion-related forebrain regions activated a VGLUT1-positive glutamatergic pathway from the dorsal peduncular cortex and dorsal tenia tecta (DP/DTT), an unexplored prefrontal cortical area, to the dorsomedial hypothalamus (DMH), a hypothalamic autonomic center. Genetic ablation and optogenetics revealed that the DP/DTT→DMH pathway drives thermogenic, hyperthermic, and cardiovascular sympathetic responses to psychosocial stress without contributing to basal homeostasis. This pathway also mediates avoidance behavior from psychosocial stressors. Given the variety of stress responses driven by the DP/DTT→DMH pathway, the DP/DTT can be a potential target for treating psychosomatic disorders.

Use of Infrared Thermography to Estimate Brown Fat Activation After a Cooling Protocol in Patients with Severe Obesity That Underwent Bariatric Surgery.

In contrast to the energy-storing role of white adipose tissue (WAT), brown adipose tissue (BAT) acts as the main site of non-shivering thermogenesis in mammals and has been reported to play a role in protection against obesity and associated metabolic alterations in rodents. Infrared thermography (IRT) has been proposed as a novel non-invasive, safe, and quick method to estimate BAT thermogenic activation in humans. The aim of this study is to determine whether the IRT could be a potential new tool to estimate BAT thermogenic activation in patients with severe obesity in response to bariatric surgery. Supraclavicular BAT thermogenic activation was evaluated using IRT in a cohort of 31 patients (50 ± 10years old, BMI = 44.5 ± 7.8; 15 undergoing laparoscopy sleeve gastrectomy and 16 Roux-en-Y gastric bypass) at baseline and 6months after a bariatric surgery. Clinical parameters were determined at these same time points. Supraclavicular BAT-related activity was detected in our patients by IRT after a cooling stimulus. The BAT thermogenic activation was higher at 6months after laparoscopy sleeve gastrectomy (0.06 ± 0.1 vs 0.32 ± 0.1), while patients undergoing to a roux-en-Y gastric bypass did not change their thermogenic response using the same cooling stimulus (0.09 ± 0.1 vs 0.08 ± 0.1). Our study postulates the IRT as a potential tool to evaluate BAT thermogenic activation in patients with obesity before and after a bariatric surgery. Further studies are needed to evaluate differences between LSG technique and RYGB on BAT activation.