المؤلفون: Vojtěch Škop, Naili Liu, Cuiying Xiao, Emma Stinson, Kong Y. Chen, Kevin D. Hall, Paolo Piaggi, Oksana Gavrilova, Marc L. Reitman

المصدر: Molecular Metabolism, Vol 84, Iss , Pp 101946- (2024)

مصطلحات موضوعية: Ultradian and circadian rhythms, Contributors to energy expenditure, Body temperature regulation, Sleep/wake, Brown adipose tissue, Physical activity and physical activity energy expenditure, Internal medicine, RC31-1245

الوصف: Our circadian world shapes much of metabolic physiology. In mice ∼40% of the light and ∼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000772Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/623d031681324e7cb1d82d3498049f9dTest

المؤلفون: Frederike J. Graelmann, Fabian Gondorf, Yasmin Majlesain, Birte Niemann, Katarina Klepac, Dominic Gosejacob, Marlene Gottschalk, Michelle Mayer, Irina Iriady, Philip Hatzfeld, Sophie K. Lindenberg, Klaus Wunderling, Christoph Thiele, Zeinab Abdullah, Wei He, Karsten Hiller, Kristian Händler, Marc D. Beyer, Thomas Ulas, Alexander Pfeifer, Charlotte Esser, Heike Weighardt, Irmgard Förster, Laia Reverte-Salisa

المصدر: Molecular Metabolism, Vol 85, Iss , Pp 101963- (2024)

مصطلحات موضوعية: Metabolic dysfunction, Indole-3-carbinol, Collagen deposition, Energy expenditure, Macrophage metabolism, Hepatic steatosis, Internal medicine, RC31-1245

الوصف: Objective: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating xenobiotic responses as well as physiological metabolism. Dietary AhR ligands activate the AhR signaling axis, whereas AhR activation is negatively regulated by the AhR repressor (AhRR). While AhR-deficient mice are known to be resistant to diet-induced obesity (DIO), the influence of the AhRR on DIO has not been assessed so far. Methods: In this study, we analyzed AhRR−/− mice and mice with a conditional deletion of either AhRR or AhR in myeloid cells under conditions of DIO and after supplementation of dietary AhR ligands. Moreover, macrophage metabolism was assessed using Seahorse Mito Stress Test and ROS assays as well as transcriptomic analysis. Results: We demonstrate that global AhRR deficiency leads to a robust, but not as profound protection from DIO and hepatosteatosis as AhR deficiency. Under conditions of DIO, AhRR−/− mice did not accumulate TCA cycle intermediates in the circulation in contrast to wild-type (WT) mice, indicating protection from metabolic dysfunction. This effect could be mimicked by dietary supplementation of AhR ligands in WT mice. Because of the predominant expression of the AhRR in myeloid cells, AhRR-deficient macrophages were analyzed for changes in metabolism and showed major metabolic alterations regarding oxidative phosphorylation and mitochondrial activity. Unbiased transcriptomic analysis revealed increased expression of genes involved in de novo lipogenesis and mitochondrial biogenesis. Mice with a genetic deficiency of the AhRR in myeloid cells did not show alterations in weight gain after high fat diet (HFD) but demonstrated ameliorated liver damage compared to control mice. Further, deficiency of the AhR in myeloid cells also did not affect weight gain but led to enhanced liver damage and adipose tissue fibrosis compared to controls. Conclusions: AhRR-deficient mice are resistant to diet-induced metabolic syndrome. Although conditional ablation of either the AhR or AhRR in myeloid cells did not recapitulate the phenotype of the global knockout, our findings suggest that enhanced AhR signaling in myeloid cells deficient for AhRR protects from diet-induced liver damage and fibrosis, whereas myeloid cell-specific AhR deficiency is detrimental.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000942Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/0c77233a1c3641c5b95ff046ca0f1936Test

المؤلفون: Rashmita Basu, Andrew J. Elmendorf, Betty Lorentz, Connor A. Mahler, Olivia Lazzaro, Britany App, Shudi Zhou, Yura Yamamoto, Mya Suber, Jamie C. Wann, Hyun Cheol Roh, Patrick L. Sheets, Travis S. Johnson, Jonathan N. Flak

المصدر: Molecular Metabolism, Vol 84, Iss , Pp 101951- (2024)

مصطلحات موضوعية: Energy expenditure, Ventromedial hypothalamic nucleus, Thermogenesis, Preoptic area, Obesity, Pituitary adenylate cyclase activating peptide, Internal medicine, RC31-1245

الوصف: Objective: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established. Methods: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips. Results: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue. Conclusions: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000826Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/c026ee79725f4b378449c51c7e720e70Test

المؤلفون: Kazuhiro Nomura, Shinichi Kinoshita, Nao Mizusaki, Yoko Senga, Tsutomu Sasaki, Tadahiro Kitamura, Hiroshi Sakaue, Aki Emi, Tetsuya Hosooka, Masahiro Matsuo, Hitoshi Okamura, Taku Amo, Alexander M. Wolf, Naomi Kamimura, Shigeo Ohta, Tomoo Itoh, Yoshitake Hayashi, Hiroshi Kiyonari, Anna Krook, Juleen R. Zierath, Masato Kasuga, Wataru Ogawa

المصدر: Molecular Metabolism, Vol 86, Iss , Pp 101968- (2024)

مصطلحات موضوعية: PGC-1α, Skeletal muscle, Exercise, Obesity, Diabetes, Energy expenditure, Internal medicine, RC31-1245

الوصف: The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000991Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/17003285f15f45a0a37f5fca4575d05cTest

المؤلفون: Nathan C. Winn, Michael W. Schleh, Jamie N. Garcia, Louise Lantier, Owen P. McGuinness, Joslin A. Blair, Alyssa H. Hasty, David H. Wasserman

المصدر: Molecular Metabolism, Vol 81, Iss , Pp 101901- (2024)

مصطلحات موضوعية: Insulin action, Insulin resistance, Insulin clamp, Glucose fluxes, Energy expenditure, Thermoregulation, Internal medicine, RC31-1245

الوصف: Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose fluxes. Short-term and adaptive responses to thermoneutral temperature (TN, ∼28 °C) and room (laboratory) temperature (RT, ∼22 °C) were studied in mice. This range of temperature does not cause detectable changes in circulating catecholamines or shivering and postabsorptive glucose homeostasis is maintained. We tested the hypothesis that a decrease in EE that occurs with TN causes insulin resistance and that this reduction in insulin action and EE is reversed upon short term (

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000322Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/2f51ca3484694f5b8883840b5ba0654eTest

المؤلفون: Mengting Jia, Siqi Liu, Yang Xiao, Zhiwang Zhang, Mingming Li, Xinyu Qi, Xinyi Qi, Lin Yu, Caiyong Zhang, Tianyu Jiang, Tingli Pan, Yu Sun, Jingsu Yu, Songtao Su, Yixing Li, Turtushikh Damba, Khongorzul Batchuluun, Yunxiao Liang, Lei Zhou

المصدر: Molecular Metabolism, Vol 80, Iss , Pp 101873- (2024)

مصطلحات موضوعية: Mcu, Obesity, Adipose tissue, Calcium homeostasis, Energy expenditure, Mitoxantrone, Internal medicine, RC31-1245

الوصف: Objective: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue. Methods: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet. Results: We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity. Conclusions: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000048Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/cf0127112f1449edb0e6be0f70bbc395Test

المؤلفون: Jennifer D. Deem, David Tingley, Christina A. Watts, Kayoko Ogimoto, Caeley L. Bryan, Bao Anh N. Phan, Vincent Damian, Michael R. Bruchas, Jarrad M. Scarlett, Michael W. Schwartz, Gregory J. Morton

المصدر: Molecular Metabolism, Vol 78, Iss , Pp 101835- (2023)

مصطلحات موضوعية: AgRP neurons, Core temperature, Energy expenditure, Energy intake, High-fat diet, Thermoregulation, Internal medicine, RC31-1245

الوصف: Objective: Preserving core body temperature across a wide range of ambient temperatures requires adaptive changes of thermogenesis that must be offset by corresponding changes of energy intake if body fat stores are also to be preserved. Among neurons implicated in the integration of thermoregulation with energy homeostasis are those that express both neuropeptide Y (NPY) and agouti-related protein (AgRP) (referred to herein as AgRP neurons). Specifically, cold-induced activation of AgRP neurons was recently shown to be required for cold exposure to increase food intake in mice. Here, we investigated how consuming a high-fat diet (HFD) impacts various adaptive responses to cold exposure as well as the responsiveness of AgRP neurons to cold. Methods: To test this, we used immunohistochemistry, in vivo fiber photometry and indirect calorimetry for continuous measures of core temperature, energy expenditure, and energy intake in both chow- and HFD-fed mice housed at different ambient temperatures. Results: We show that while both core temperature and the thermogenic response to cold are maintained normally in HFD-fed mice, the increase of energy intake needed to preserve body fat stores is blunted, resulting in weight loss. Using both immunohistochemistry and in vivo fiber photometry, we show that although cold-induced AgRP neuron activation is detected regardless of diet, the number of cold-responsive neurons appears to be blunted in HFD-fed mice. Conclusions: We conclude that HFD-feeding disrupts the integration of systems governing thermoregulation and energy homeostasis that protect body fat mass during cold exposure.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877823001692Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/7556e099c97e49cabbcd44cff2dcf9ccTest

المؤلفون: Heike Münzberg, Hans-Rudolf Berthoud, Winfried L. Neuhuber

المصدر: Molecular Metabolism, Vol 78, Iss , Pp 101817- (2023)

مصطلحات موضوعية: Interoception, Food intake, Energy expenditure, Obesity, Diabetes, Gut-brain communication, Internal medicine, RC31-1245

الوصف: Interoception plays an important role in homeostatic regulation of energy intake and metabolism. Major interoceptive pathways include gut-to-brain and adipose tissue-to brain signaling via vagal sensory nerves and hormones, such as leptin. However, signaling via spinal sensory neurons is rapidly emerging as an additional important signaling pathway. Here we provide an in-depth review of the known anatomy and functions of spinal sensory pathways and discuss potential mechanisms relevant for energy balance homeostasis in health and disease. Because sensory innervation by dorsal root ganglia (DRG) neurons goes far beyond vagally innervated viscera and includes adipose tissue, skeletal muscle, and skin, it is in a position to provide much more complete metabolic information to the brain. Molecular and anatomical identification of function specific DRG neurons will be important steps in designing pharmacological and neuromodulation approaches to affect energy balance regulation in disease states such as obesity, diabetes, and cancer.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877823001515Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/548e29300ec84767a18c4e73c032f2e1Test

المؤلفون: Yang Liu, Yue Qu, Chloe Cheng, Pei-Yin Tsai, Kaydine Edwards, Siwen Xue, Supriya Pandit, Sakura Eguchi, Navneet Sanghera, Joeva J. Barrow

المصدر: Molecular Metabolism, Vol 75, Iss , Pp 101770- (2023)

مصطلحات موضوعية: Nipsnap1, Thermogenesis maintenance, Brown adipose tissue, Lipid metabolism, Energy expenditure, Internal medicine, RC31-1245

الوصف: Objective: The activation of non-shivering thermogenesis (NST) has strong potential to combat obesity and metabolic disease. The activation of NST however is extremely temporal and the mechanisms surrounding how the benefits of NST are sustained once fully activated, remain unexplored. The objective of this study is to investigate the role of 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) in NST maintenance, which is a critical regulator identified in this study. Methods: The expression of Nipsnap1 was profiled by immunoblotting and RT-qPCR. We generated Nipsnap1 knockout mice (N1–KO) and investigated the function of Nipsnap1 in NST maintenance and whole-body metabolism using whole body respirometry analyses. We evaluate the metabolic regulatory role of Nipsnap1 using cellular and mitochondrial respiration assay. Results: Here, we show Nipsnap1 as a critical regulator of long-term thermogenic maintenance in brown adipose tissue (BAT). Nipsnap1 localizes to the mitochondrial matrix and increases its transcript and protein levels in response to both chronic cold and β3 adrenergic signaling. We demonstrated that these mice are unable to sustain activated energy expenditure and have significantly lower body temperature in the face of an extended cold challenge. Furthermore, when mice are exposed to the pharmacological β3 agonist CL 316, 243, the N1–KO mice exhibit significant hyperphagia and altered energy balance. Mechanistically, we demonstrate that Nipsnap1 integrates with lipid metabolism and BAT-specific ablation of Nipsnap1 leads to severe defects in beta-oxidation capacity when exposed to a cold environmental challenge. Conclusion: Our findings identify Nipsnap1 as a potent regulator of long-term NST maintenance in BAT.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877823001047Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/f8ba1a2605c44840927d4a1a638c1d75Test

المؤلفون: A. Stefanidis, C.M.C. Lee, E. Greaves, M.K. Montgomery, M. Arnold, S. Newn, A.J. Budin, M.B. Lemus, C.J. Foldi, P.R. Burton, W.A. Brown, T.A. Lutz, M.J. Watt, B.J. Oldfield

المصدر: Molecular Metabolism, Vol 73, Iss , Pp 101739- (2023)

مصطلحات موضوعية: Bariatric surgery, Metabolic surgery, Vertical sleeve gastrectomy, Animal model, Energy expenditure, Brown adipose tissue thermogenesis, Internal medicine, RC31-1245

الوصف: Objective: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. Methods: Diet-induced obese male Sprague–Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. Results: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. Conclusions: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S221287782300073XTest; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/c88ace75766a47a391b61f006bfb37e6Test