Cold-responsive adipocyte progenitors couple adrenergic signaling to immune cell activation to promote beige adipocyte accrual.

The full array of cold-responsive cell types within white adipose tissue that drive thermogenic beige adipocyte biogenesis remains undefined. We demonstrate that acute cold challenge elicits striking transcriptomic changes specifically within DPP4+ PDGFRß+ adipocyte precursor cells, including a ß-adrenergic receptor CREB-mediated induction in the expression of the prothermogenic cytokine, Il33 Doxycycline-inducible deletion of Il33 in PDGFRß+ cells at the onset of cold exposure attenuates ILC2 accumulation and beige adipocyte accrual. These studies highlight the multifaceted roles for adipocyte progenitors and the ability of select mesenchymal subpopulations to relay neuronal signals to tissue-resident immune cells in order to regulate tissue plasticity.

The essential role of architectural noncoding RNA Neat1 in cold-induced beige adipocyte differentiation in mice.

Neat1 is an architectural RNA that provides the structural basis for nuclear bodies known as paraspeckles. Although the assembly processes by which Neat1 organizes paraspeckle components are well-documented, the physiological functions of Neat1 are not yet fully understood. This is partly because Neat1 knockout (KO) mice, lacking paraspeckles, do not exhibit overt phenotypes under normal laboratory conditions. During our search for conditions that elicit clear phenotypes in Neat1 KO mice, we discovered that the differentiation of beige adipocytes-inducible thermogenic cells that emerge upon cold exposure-is severely impaired in these mutant mice. Neat1_2, the architectural isoform of Neat1, is transiently upregulated during the early stages of beige adipocyte differentiation, coinciding with increased paraspeckle formation. Genes with altered expression during beige adipocyte differentiation typically cluster at specific chromosomal locations, some of which move closer to paraspeckles upon cold exposure. These observations suggest that paraspeckles might coordinate the regulation of these gene clusters by controlling the activity of certain transcriptional condensates that coregulate multiple genes. We propose that our findings highlight a potential role for Neat1 and paraspeckles in modulating chromosomal organization and gene expression, potentially crucial processes for the differentiation of beige adipocytes.

Immune response to cold exposure: Role of γδ T cells and TLR2-mediated inflammation.

The mammalian body possesses remarkable adaptability to cold exposure, involving intricate adjustments in cellular metabolism, ultimately leading to thermogenesis. However, cold-induced stress can impact immune response, primarily through noradrenaline-mediated pathways. In our study, we utilized a rat model subjected to short-term or long-term mild cold exposure to investigate systemic immune response during the cold acclimation. To provide human relevance, we included a group of regular cold swimmers in our study. Our research revealed complex relationship between cold exposure, neural signaling, immune response, and thermogenic regulation. One-day cold exposure triggered stress response, including cytokine production in white adipose tissue, subsequently activating brown adipose tissue, and inducing thermogenesis. We further studied systemic immune response, including the proportion of leukocytes and cytokines production. Interestingly, γδ T cells emerged as possible regulators in the broader systemic response, suggesting their possible contribution in the dynamic process of cold adaptation. We employed RNA-seq to gain further insights into the mechanisms by which γδ T cells participate in the response to cold. Additionally, we challenged rats exposed to cold with the Toll-like receptor 2 agonist, showing significant modulation of immune response. These findings significantly contribute to understanding of the physiological acclimation that occur in response to cold exposure.

Brown fat-specific mitoribosomal function is crucial for preventing cold exposure-induced bone loss.

This study examines the interplay between ambient temperature, brown adipose tissue (BAT) function, and bone metabolism, emphasizing the effects of cold exposure and BAT mitochondrial activity on bone health. Utilizing ovariectomized (OVX) mice to model primary osteoporosis and BAT-specific mitochondrial dysfunction (BKO) mice, we evaluated the impact of housing temperature on bone density, immune modulation in bone marrow, and the protective role of BAT against bone loss. Cold exposure was found to universally reduce bone mass, enhance osteoclastogenesis, and alter bone marrow T-cell populations, implicating the immune system in bone remodeling under cold stress. The thermogenic function of BAT, driven by mitochondrial oxidative phosphorylation, was crucial in protecting against bone loss. Impaired BAT function, through surgical removal or mitochondrial dysfunction, exacerbated bone loss in cold environments, highlighting BAT's metabolic role in maintaining bone health. Furthermore, cold-induced changes in BAT function led to systemic metabolic shifts, including elevated long-chain fatty acids, which influenced osteoclast differentiation and activity. These findings suggest a systemic mechanism connecting environmental temperature and BAT metabolism with bone physiology, providing new insights into the metabolic and environmental determinants of bone health. Future research could lead to novel bone disease therapies targeting these pathways.

Cold Exposure-induced Alterations in the Brain Peptidome and Gut Microbiome Are Linked to Energy Homeostasis in Mice.

Energy homeostasis of mammals during cold exposure involves complicated neural regulation and is affected by gut microbiota. However, the regulatory mechanism remains unclear partially due to a lack of comprehensive knowledge of the signaling molecules involved. Herein, we performed region-resolvable quantitative profiling of the brain peptidome using cold-exposed mouse models and interrogated the interaction between gut microbes and brain peptides in response to cold. Region-specific alterations in the brain peptidome were observed during chronic cold exposure and were correlated with gut microbiome composition. Several proSAAS-derived peptides exhibited a positive correlation with Lactobacillus. The hypothalamus-pituitary axis exhibited a sensitive response to cold exposure. We obtained a candidate pool of bioactive peptides that potentially participate in the regulation of cold-induced energy homeostasis. Intervention with cold-adapted microbiota in mice decreased the abundance of hypothalamic neurokinin B and subsequently contributed to shifting the fuel source for energy consumption from lipids to glucose. Collectively, this study demonstrated that gut microbes modulate brain peptides contributing to energy metabolism, providing a data resource for understanding the regulatory mechanism of energy homeostasis upon cold exposure.

SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.

Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.

Identification of regulatory networks and crosstalk factors in brown adipose tissue and liver of a cold-exposed cardiometabolic mouse model.

BACKGROUND: Activation of brown adipose tissue (BAT) has gained attention due to its ability to dissipate energy and counteract cardiometabolic diseases (CMDs). METHODS: This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days. RESULTS: We identified several dysregulated pathways, miRNAs, and transcription factors in BAT and liver of cold-exposed Ldlrko mice that have not been previously described in this context. Networks of regulatory interactions based on shared downstream targets and analysis of ligand-receptor pairs identified fibrinogen alpha chain (FGA) and fibronectin 1 (FN1) as potential crosstalk factors between BAT and liver in response to cold exposure. Importantly, genetic variations in the genes encoding FGA and FN1 have been associated with cardiometabolic-related phenotypes and traits in humans. DISCUSSION: This study describes the key factors, pathways, and regulatory networks involved in the crosstalk between BAT and the liver in a cold-exposed CMD mouse model. These findings may provide a basis for future studies aimed at testing whether molecular mediators, as well as regulatory and signaling mechanisms involved in tissue adaption upon cold exposure, could represent a target in cardiometabolic disorders.

Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy.

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

The application of heating film to hands reduces the decline in manual dexterity performance associated with cold exposure.

PURPOSE: Exposure to cold temperatures decreases finger temperature (Tfing) and dexterity. Decreased manual function and dexterity can be serious safety risks, especially in tasks that require fine motor movements that must be performed outdoors. The aim of this study was to determine whether hand heating with a minimal power requirement (14.8 W) results in a smaller reduction in Tfing and manual dexterity performance during mild cold exposure compared to a non-heated control condition. METHODS: In a randomized crossover design, twenty-two healthy participants were exposed to a moderately cold environment (5  ºC) for 90 min. One condition had no intervention (CON), while the other had the palmar and dorsal hands heated (HEAT) by using electric heating films. Tfing and cutaneous vascular conductance (CVC) were continuously monitored using laser Doppler flowmetry. Manual dexterity performance and cognitive function were assessed by the Grooved Pegboard Test (GPT) and Stroop Color-Word (SCW) test, respectively, during the baseline period and every 30 min during the cold exposure. RESULTS: After the cold exposure, Tfing was higher in HEAT relative to CON (CON 9.8 vs. HEAT 13.7 ºC, p < 0.0001). GPT placing time, as an index of dexterity performance, was also shorter in HEAT by 14.5% (CON 69.10 ± 13.08 vs. HEAT 59.06 ± 7.99 s, p < 0.0001). There was no difference in CVC between the two conditions during the cold exposure (p > 0.05 for all). Cognitive function was similar between two conditions (p > 0.05 for all). CONCLUSION: The proposed hand heating method offers a practical means of heating fingers to maintain dexterity throughout prolonged cold exposure.

Mitophagy Responds to the Environmental Temperature and Regulates Mitochondrial Mass in Adipose Tissues.

There are at least two types of adipose tissues in the body, defined as brown adipose tissues (BATs) and white adipose tissues (WATs). These tissues comprise brown and white adipocytes, respectively. The adipocytes are commonly endowed with mitochondria, but they have diverse characteristics and roles. Brown adipocytes have abundant mitochondria that contribute to the ß-oxidation of fatty acids to produce chemical energy and the production of heat via uncoupling of the mitochondrial membrane potential from ATP synthesis. Alternatively, white adipocytes have fewer mitochondria that contribute to the generation of free fatty acids via lipogenesis by providing key intermediates. Besides the described types of adipocytes, brown-like adipocytes, termed beige adipocytes, are developed in WAT depots during cold exposure. Beige adipocytes also contribute to thermogenesis. Notably, beige adipocytes may transform into white-like adipocytes after the withdrawal of cold exposure. This process is marked by the elimination of mitochondria through the activation of mitochondria autophagy (mitophagy). This review aims to describe the mitophagy that occurs during the beige-to-white transition and discuss recent insights into the molecular mechanisms of this transformation. Additionally, we describe the mitophagy monitoring strategy in adipose tissues using three independent reporter systems and discuss the availabilities and limitations of the method.

Cold exposure alters lipid metabolism of skeletal muscle through HIF-1α-induced mitophagy.

BACKGROUND: In addition to its contractile properties and role in movement, skeletal muscle plays an important function in regulating whole-body glucose and lipid metabolism. A central component of such regulation is mitochondria, whose quality and function are essential in maintaining proper metabolic homeostasis, with defects in processes such as autophagy and mitophagy involved in mitochondria quality control impairing skeletal muscle mass and function, and potentially leading to a number of associated diseases. Cold exposure has been reported to markedly induce metabolic remodeling and enhance insulin sensitivity in the whole body by regulating mitochondrial biogenesis. However, changes in lipid metabolism and lipidomic profiles in skeletal muscle in response to cold exposure are unclear. Here, we generated lipidomic or transcriptome profiles of mouse skeletal muscle following cold induction, to dissect the molecular mechanisms regulating lipid metabolism upon acute cold treatment. RESULTS: Our results indicated that short-term cold exposure (3 days) can lead to a significant increase in intramuscular fat deposition. Lipidomic analyses revealed that a cold challenge altered the overall lipid composition by increasing the content of triglyceride (TG), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE), while decreasing sphingomyelin (SM), validating lipid remodeling during the cold environment. In addition, RNA-seq and qPCR analysis showed that cold exposure promoted the expression of genes related to lipolysis and fatty acid biosynthesis. These marked changes in metabolic effects were associated with mitophagy and muscle signaling pathways, which were accompanied by increased TG deposition and impaired fatty acid oxidation. Mechanistically, HIF-1α signaling was highly activated in response to the cold challenge, which may contribute to intramuscular fat deposition and enhanced mitophagy in a cold environment. CONCLUSIONS: Overall, our data revealed the adaptive changes of skeletal muscle associated with lipidomic and transcriptomic profiles upon cold exposure. We described the significant alterations in the composition of specific lipid species and expression of genes involved in glucose and fatty acid metabolism. Cold-mediated mitophagy may play a critical role in modulating lipid metabolism in skeletal muscle, which is precisely regulated by HIF-1α signaling.

The effects of cold exposure (cold water immersion, whole- and partial- body cryostimulation) on cardiovascular and cardiac autonomic control responses in healthy individuals: A systematic review, meta-analysis and meta-regression.

BACKGROUND: Cryostimulation and cold-water immersion (CWI) have recently gained widespread attention due to their association with changes in cardiovascular and cardiac autonomic control responses. Therefore, the aim of the present systematic review and meta-analysis was to identify the global impact of such cold exposures on cardiovascular and cardiac autonomic activity. METHODS: Three databases (PubMed, Embase, Web-of-Science) were used. Studies were eligible for inclusion if they were conducted on healthy participants using cryostimulation and/or CWI. The outcomes included measurements of blood pressure (BP), heart rate (HR), and heart rate variability (HRV) indices: RR interval (RR), Root mean square of successive RR interval differences (RMSSD), low frequency band (LF), high frequency band (HF), and LF/HF ratio. RESULTS: Among the 27 articles included in our systematic literature review, only 24 were incorporated into the meta-analysis. Our results reveal a significant increase in HRV indices: RMSSD (Standardized mean difference (SMD) = 0.61, p < 0.001), RR (SMD = 0.77, p < 0.001), and HF (SMD = 0.46, p < 0.001), as well as significantly reduced LF (SMD = -0.41, p < 0.001) and LF/HF ratio (SMD = -0.25, p < 0.01), which persisted up to 15 min following cold exposure. Significantly decreased heart rate (SMD = -0.16, p < 0.05), accompanied by slightly increased mean BP (SMD = 0.28, p < 0.001), was also observed. These results seem to depend on individual characteristics and the cooling techniques. CONCLUSION: Our meta-analysis suggests that cryostimulation and/or CWI exposure enhance parasympathetic nervous activity. There is scarce scientific literature regarding the effect of individual characteristics on cold-induced physiological responses.

Therapeutic Potential of Salvia miltiorrhiza Root Extract in Alleviating Cold-Induced Immunosuppression.

The interaction between environmental stressors, such as cold exposure, and immune function significantly impacts human health. Research on effective therapeutic strategies to combat cold-induced immunosuppression is limited, despite its importance. In this study, we aim to investigate whether traditional herbal medicine can counteract cold-induced immunosuppression. We previously demonstrated that cold exposure elevated immunoglobulin G (IgG) levels in mice, similar to the effects of intravenous immunoglobulin (IVIg) treatments. This cold-induced rise in circulating IgG was mediated by the renin-angiotensin-aldosterone system and linked to vascular constriction. In our mouse model, the cold-exposed groups (4 °C) showed significantly elevated plasma IgG levels and reduced bacterial clearance compared with the control groups maintained at room temperature (25 °C), both indicative of immunosuppression. Using this model, with 234 mice divided into groups of 6, we investigated the potential of tanshinone IIA, an active compound in Salvia miltiorrhiza ethanolic root extract (SMERE), in alleviating cold-induced immunosuppression. Tanshinone IIA and SMERE treatments effectively normalized elevated plasma IgG levels and significantly improved bacterial clearance impaired by cold exposure compared with control groups injected with a vehicle control, dimethyl sulfoxide. Notably, bacterial clearance, which was impaired by cold exposure, showed an approximately 50% improvement following treatment, restoring immune function to levels comparable to those observed under normal temperature conditions (25 °C, p < 0.05). These findings highlight the therapeutic potential of traditional herbal medicine in counteracting cold-induced immune dysregulation, offering valuable insights for future strategies aimed at modulating immune function in cold environments. Further research could focus on isolating tanshinone IIA and compounds present in SMERE to evaluate their specific roles in mitigating cold-induced immunosuppression.

Deaths due to suspected hypothermia in sheep and alpacas on a Manawatu farm in New Zealand in mid-summer.

CASE HISTORY: In mid-summer (February), 42 of a flock of 68 ram hoggets (approximately 5 months of age) and two of a group of 14 alpacas on a farm in the Manawatu region of New Zealand were found recumbent or dead following a period of persistent rain, strong winds and relatively low temperatures. The hoggets and alpacas had been shorn 4 and 53 days previously, respectively, and were in adequate to good body condition with access to ad libitum pasture. Post-mortem and histological examinations were undertaken on four hoggets and two alpacas. CLINICAL FINDINGS: Apart from hypothermic body temperatures from four recumbent hoggets, nothing of significance was identified on clinical or gross pathological examination. Histological changes of vacuolar hepatopathy, renal tubular degeneration and pulmonary congestion were present in all animals examined. DIAGNOSIS: Based on the history and clinical and pathological findings, hypothermia was highly probable to have been the cause of the deaths. CLINICAL RELEVANCE: These cases emphasise the importance of shelter for recently shorn sheep and alpacas regardless of the season.

Keep Cool but Don't Freeze: The Influence of William J. Mills Jr. on the Treatment of Frostbite.

Dr William J. Mills Jr., an Alaskan orthopedic surgeon, helped establish the current protocols for frostbite treatment and changed a dogma used for more than 140 years that was established by Napoleon's surgeon general of the army, Baron Dominique-Jean Larrey. During Napoleon's 1812 siege of Moscow, Larrey noticed the destructive effects of using open fire heat for warming frozen body parts, so he suggested rubbing snow or immersion in cold water. Dr Mills treated many cold injuries during his medical career. After setting up his medical practice in Anchorage, Alaska, he realized the inefficiency of the established protocols and started researching new treatments for frostbite. Dr Mills followed Meryman's method of rapidly thawing frozen red blood cells in warm water. Mills and his colleagues established a treatment protocol for freezing cold injury that included rapid warming in warm water. These studies resulted in the publication of three key papers in 1960 and 1961. These papers were the first clinical studies that described rapid warming as a treatment. Subsequently, rapid warming, with some variation in water temperatures, has been accepted as the standard of treatment. Due to his outstanding contribution to the treatment of frostbite, he has been referred to as "the nation's leading authority on cold injury." Mills and his colleagues created a new classification system that divided frostbite into two levels, superficial and deep, which was more applicable in clinics than the traditional 4-tier classification. The 2-tier classification is still useful outside of the hospital setting.

Cold-Induced Vasodilation, Rewarming, and Dexterity Impairment Following Second-Degree Frostbite.

Frostbite, a severe cold injury resulting from exposure to subfreezing temperatures, damages the skin and underlying tissues of the affected area and ranges in severity from first to fourth degree. This case report investigates the impact of second-degree frostbite suffered by a marine during winter training on cold-induced vasodilation (CIVD). Comparisons of CIVD before and after the injury revealed significant alterations in CIVD responses. CIVD, a physiological mechanism characterized by blood vessel dilation in response to cold exposure, plays a crucial role in operating in cold-weather environments and enhancing dexterity. The marine exhibited prolonged CIVD onset time, lower finger temperatures, increased pain sensations, and diminished dexterity after the frostbite injury during follow-up CIVD testing. The findings suggest that the frostbite-induced damage possibly compromised the microvascular function, contributing to the observed changes in CIVD. The marine reported persistent cold sensitivity and difficulty in maintaining hand warmth when assessed postinjury. This case underscores the potential long-term consequences of frostbite on CIVD and manual dexterity, emphasizing the importance of understanding these physiological changes for individuals engaged in cold-weather activities, particularly for military and occupational personnel.

Cold Exposure and the Metabolism of Mice, Men, and Other Wonderful Creatures.

Laboratory rodents and cold-adapted animals in the wild use a significant amount of the energy derived from food intake for heat generation. Thermogenesis involving mitochondrial uncoupling in the brown adipose tissue differs quantitatively in mice, humans, and cold-adapted animals and could be an important ally to combat obesity if humans were prepared to deviate slightly from thermoneutral living conditions to activate this pathway.

CCE and EODF as two distinct non-shivering thermogenesis models inducing weight loss.

Increasing energy expenditure and reducing energy intake are considered two classical methods to induce weight loss. Weight loss through physical methods instead of drugs has been a popular research topic nowadays, but how these methods function in adipose and cause weight loss in body remains unclear. In this study, we set up chronic cold exposure (CCE) and every-other-day fasting (EODF) as two distinct models in long-term treatment to induce weight loss, recording their own characteristics in changes of body temperature and metabolism. We investigated the different types of non-shivering thermogenesis induced by CCE and EODF in white and brown adipose tissue through sympathetic nervous system (SNS), creatine-driven pathway, and fibroblast growth factor 21 (FGF21)-adiponectin axis. CCE and EODF could reduce body weight, lipid composition, increase insulin sensitivity, promote the browning of white fat, and increase the expression of endogenous FGF21 in adipose tissue. CCE stimulated the SNS and increased the thermogenic function of brown fat, and EODF increased the activity of protein kinase in white fat. In this study, we further explained the thermogenic mechanism function in adipose and metabolic benefits of the stable phenotype through physical treatments used for weight loss, providing more details for the literature on weight loss models. The influence on metabolism, non-shivering thermogenesis, endogenous FGF21, and ADPN changes in the long-term treatment of distinct methods (increasing energy expenditure and decreasing energy intake) to induce weight loss.

Image registration and mutual thresholding enable low interimage variability across dynamic MRI measurements of supraclavicular brown adipose tissue during mild cold exposure.

PURPOSE: Activated brown adipose tissue (BAT) enhances lipid catabolism and improves cardiometabolic health. Quantitative MRI of the fat fraction (FF) of supraclavicular BAT (scBAT) is a promising noninvasive measure to assess BAT activity but suffers from high scan variability. We aimed to test the effects of coregistration and mutual thresholding on the scan variability in a fast (1 min) time-resolution MRI protocol for assessing scBAT FF changes during cold exposure. METHODS: Ten volunteers (age 24.8 ± 3.0 years; body mass index 21.2 ± 2.1 kg/m2 ) were scanned during thermoneutrality (32°C; 10 min) and mild cold exposure (18°C; 60 min) using a 12-point gradient-echo sequence (70 consecutive scans with breath-holds, 1.03 min per dynamic). Dynamics were coregistered to the first thermoneutral scan, which enabled drawing of single regions of interest in the scBAT depot. Voxel-wise FF changes were calculated at each time point and averaged across regions of interest. We applied mutual FF thresholding, in which voxels were included if their FF was greater than 30% FF in the reference scan and the registered dynamic. The efficacy of the coregistration was determined by using a moving average and comparing the mean squared error of residuals between registered and nonregistered data. Registered scBAT ΔFF was compared with single-scan thresholding using the moving average method. RESULTS: Registered scBAT ΔFF had lower mean square error values than nonregistered data (0.07 ± 0.05% vs. 0.16 ± 0.14%; p < 0.05), and mutual thresholding reduced the scBAT ΔFF variability by 30%. CONCLUSION: We demonstrate that coregistration and mutual thresholding improve stability of the data 2-fold, enabling assessment of small changes in FF following cold exposure.

Maternal L-carnitine supplementation promotes brown adipose tissue thermogenesis of newborn goats after cold exposure.

Brown adipose tissue (BAT) is an important component of energy expenditure and necessary to maintain body temperature for newborn mammals. In the previous study, we found that L-carnitine was enriched in BAT and promoted BAT adipogenesis and thermogenesis in goat brown adipocytes. However, whether dietary L-carnitine regulates BAT heat production and energy expenditure in lambs remains unclear. In this study, maternal L-carnitine supplementation elevated the rectal temperature, as well as the expression of UCP1 and mitochondrial DNA content to promote BAT thermogenesis in newborn goats. Moreover, maternal L-carnitine supplementation increased the levels of triglycerides (TG), non-esterified fatty acids (NEFA), and lactate in plasma, as well as the content of lipid droplet and glycogen in BAT of newborn goats. Lipidomic analysis showed that maternal L-carnitine supplementation remodeled the lipid composition of BAT in newborn goats. L-carnitine significantly increased the levels of TG and diglyceride (DG) and decreased the levels of glycerophospholipids and sphingolipids in BAT. Further studies showed that L-carnitine promoted TG and glycogen deposition in brown adipocytes through AMPKα. Our results indicate that maternal L-carnitine supplementation promotes BAT development and thermogenesis in newborn goats and provides new evidence for newborn goats to maintain body temperature in response to cold exposure.