Uncoupling Protein Research Articles

The modulatory effect of oat on brain-derived neurotrophic factor, orexigenic neuropeptides, and dopaminergic signaling in obesity-induced rat model: a comparative study to orlistat.

Obesity is a non-communicable complex disease that is the fifth leading cause of death worldwide. According to a novel viewpoint, the brain plays a significant role in the central regulation of satiety and energy homeostasis. Because of its rich nutritional profile and versatile uses, oat (Avena sativa) is one of the most popular functional foods recommended by many nutritionists. The anti-obesity effect of oat was hypothesized, focusing on the brain as the target organ. In the current study, the interplay between brain biomarkers, obesity, and its related complications was evaluated in diet-induced obese rats for 25 weeks, in which 60 adult male white albino Wistar rats were divided into three control and seven treatment groups given oat extracts in a dose-dependent manner. Oat significantly improved obesity-related metabolic complications. In terms of brain function, oat significantly increased dopaminergic signaling, brain-derived neurotrophic factor levels, vaspin, irisin, and uncoupling protein-1 brain levels, while decreasing the expression of agouti-related peptide and neuropeptide Y (P-value < 0.05). The current study proposes oat supplementation as a new conceptual framework with numerous implications for hedonic and homeostatic mechanisms that control satiety. © 2024 Society of Chemical Industry.

High lipolytic capacity improves cold tolerance in red swamp crayfish (Procambarus clarkii)

Temperature is one of the most prevalent environmental factors that affects the growth and development of organisms. The survival of aquatic animals is closely related to the changes in temperature, low temperature could cause physiological damage even death. In this study, we revealed the regulatory mechanisms of low-temperature stimulation from the transcriptomics in the hepatopancreas of the red swamp crayfish, Procambarus clarkii. Transcriptome sequencing revealed that lipid metabolism pathways were significantly enriched at low temperature. Crayfish improved their cold tolerance by increasing expression levels of thermogenic gene prdm16 and uncoupling protein genes ucp4 and ucp5. Furthermore, lipid and triglyceride content increased significantly in cold-sensitive crayfish, which in turn increased the expression levels of proinflammatory factors (cox2 and tgfβr) and the amount of hepatopancreas bacteria. In addition, low-temperature stimulation could cause more severe damage to cold-sensitive crayfish spermatophores, accompanied by downregulated of spermatozoa viability-related genes such as alp and ldh. Estradiol 17β-dehydrogenase 8-like (17βde8) may contain a critical SNP site at exon 544, the bases of this site were “G” in cold-tolerant crayfish and “A” in cold-sensitive crayfish. Above all, our results reveal that lipid metabolism is the main factor affecting cold tolerance in crayfish and reveal the key loci for cold tolerance, providing a reference for cold tolerance breeding.

CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity

ObjectiveBrown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of Ucp1 with a long 3′-untranslated region (Ucp1L) in response to adrenergic signaling. Mice lacking CPEB2 or Ucp1L exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes. Hence, this study aims to investigate how CPEB2-controlled translation impacts body weight. MethodsBody weight measurements were conducted on mice with global knockout (KO) of CPEB2, UCP1 or Ucp1L, as well as those with conditional knockout of CPEB2 in neurons or adipose tissues. RNA sequencing coupled with bioinformatics analysis was used to identify dysregulated gene expression in CPEB2-deficient BAT. The role of CPEB2 in regulating PRD1-BF1-RIZ1 homologous-domain containing 16 (PRDM16) expression was subsequently confirmed by RT-qPCR, Western blotting, polysomal profiling and luciferase reporter assays. Adeno-associated viruses (AAV) expressing CPEB2 or PRDM16 were delivered into BAT to assess their efficacy in mitigating weight gain in CPEB2-KO mice. ResultsWe validated that defective BAT function contributed to the increased weight gain in CPEB2-KO mice. Transcriptomic profiling revealed upregulated expression of genes associated with muscle development in CPEB2-KO BAT. Given that both brown adipocytes and myocytes stem from myogenic factor 5-expressing precursors, with their cell-fate differentiation regulated by PRDM16, we identified that Prdm16 was translationally upregulated by CPEB2. Ectopic expression of PRDM16 in CPEB2-deprived BAT restored gene expression profiles and decreased weight gain in CPEB2-KO mice. ConclusionsIn addition to Ucp1L, activation of Prdm16 translation by CPEB2 is critical for sustaining brown adipocyte function. These findings unveil a new layer of post-transcriptional regulation governed by CPEB2, fine-tuning thermogenic and metabolic activities of brown adipocytes to control body weight.

IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called “reverse mode” of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

The Role of Matrix Stiffness And Viscosity on Lipid Phenotype And Fat Lineage Potential.

Autologous fat transfer is a common procedure that patients undergo to rejuvenate large soft tissue defects. However, these surgeries are complicated by limited tissue sources, donor-site morbidity, and necrosis. While the biofabrication of fat tissue can serve as a clinical option for reconstructive surgery, the influence of matrix mechanics, specifically stiffness and viscosity, on adipogenesis requires further elucidation. Additionally, the effects of these mechanical parameters on metabolic and thermogenic fat potential haveyet to be investigated. In this study, gelatinmethacryloyl (GelMA) polymers with varying degrees of methacrylation (DoM) were fabricated to create matrices with different stiffnesses and viscosities. Human adipose-derived mesenchymal stem cells were then encapsulated in mechanically tunable GelMA and underwent adipogenesis to investigate the effects of matrix mechanics on lipid phenotype and fat potential. Mechanical testing confirmed that GelMA stiffness was regulated by DoM and weight composition, whereas viscosity was determined by the latter. Further work revealed that while lipid phenotype became more enriched as matrix stiffness and viscosity declined, the potential toward metabolic and thermogenic fat appeared to be more viscous dependent rather than stiffness dependent. In addition, fatty acid binding protein 4 and uncoupling protein 1 gene expression exhibited viscous-dependent behavior despite comparable levels of peroxisome proliferator-activated receptor gamma. However, despite the superior role of viscosity, lipid quantity and mitochondrial abundance demonstrated stiffness-dependent behavior. Overall, this work revealed that matrix viscosity played a more superior role than stiffness in driving adipogenesis and distinguishing between metabolic and thermogenic fat potential. Ultimately, this differentiation in fat production is important for engineering ideal adipose tissue for large soft tissue defects.

Maid gene dysfunction promotes hyperobesity via the reduction of adipose tissue inflammation in Mc4r gene-deficient mice

The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice.

Reduction of hyperglycemia in STZ-induced diabetic mice by prophylactic treatment with heat-killed Mycobacterium aurum: possible effects on glucose utilization, mitochondrial uncoupling, and oxidative stress in liver and skeletal muscle.

In addition to conventional treatment and modifications in physical activity and diet, alternative strategies have been investigated to manage, prevent, or delay diabetes in humans. In this regard, one strategy has relied on the immunomodulatory properties of mycobacteria, whereby Bacillus Calmette-Guerin, an attenuated live strain of Mycobacterium bovis, has been shown to improve glycemic control in patients with diabetes and to alleviate hyperglycemia in selected murine models of diabetes. A novel heat-killed (HK) whole-cell preparation of Mycobacterium aurum (M. aurum) is currently under development as a potential food supplement; nevertheless, its potential bioactivity remains largely unknown. Thus, the present study investigated the potential prophylactic anti-diabetic effects of HK M. aurum in streptozotocin (STZ)-induced diabetic mice. Mice were divided into three groups: the STZ-induced diabetic group was injected with a single intraperitoneal high dose of STZ, the HK M. aurum-treated diabetic group was prophylactically treated with three doses of HK M. aurum 6 weeks before STZ injection, and the control non-diabetic group was given three intradermal injections of borate-buffered saline and an intraperitoneal injection of citrate buffer. Liver lactate dehydrogenase (LDH), uncoupling protein 2 (UCP2), and glucose transporter 2 (GLUT2) and skeletal muscle LDH, UCP3, and GLUT4 protein expression levels in different mouse groups were determined by Western blot. Our results indicated that HK M. aurum did not cause any significant changes in glycemic levels of normal non-diabetic mice. Prophylactic administration of three doses of HK M. aurum to diabetic mice resulted in a significant reduction in their blood glucose levels when compared to those in control diabetic mice. Prophylactic treatment of diabetic mice with HK M. aurum significantly restored their disturbed protein expression levels of liver UCP2 and LDH as well as of skeletal muscle UCP3. On the other hand, prophylactic treatment of diabetic mice with HK M. aurum had no significant effect on their liver GLUT2 and skeletal muscle GLUT4 and LDH protein expression levels. Our findings provide the first evidence that HK M. aurum possesses a hyperglycemia-lowering capacity and might support its future use as a food supplement for the amelioration of diabetes.

Characterization of Ucp1-iCre knockin mice reveals the recombination activity in male germ cells.

Ucp1 promoter-driven Cre transgenic mice are useful in the manipulation of gene expression specifically in thermogenic adipose tissues. However, the wildly used Ucp1-Cre line was generated by random insertion into the genome and showed ectopic activity in some tissues beyond adipose tissues. Here, we characterized a knockin mouse line Ucp1-iCre generated by targeting IRES-Cre cassette immediately downstream the stop codon of the Ucp1 gene. The Cre insertion had little to no effect on uncoupling protein 1 (UCP1) levels in brown adipose tissue. Ucp1-iCre mice of both genders exhibited normal thermogenesis and cold tolerance. When crossed with Rosa-tdTomato reporter mice, Ucp1-iCre mice showed robust Cre activity in thermogenic adipose tissues. In addition, limited Cre activity was sparsely present in the ventromedial hypothalamus (VMH), choroid plexus, kidney, adrenal glands, ovary, and testis in Ucp1-iCre mice, albeit to a much lesser extent and with reduced intensity compared with the conventional Ucp1-Cre line. Single-cell transcriptome analysis revealed Ucp1 mRNA expression in male spermatocytes. Moreover, male Ucp1-iCre mice displayed a high frequency of Cre-mediated recombination in the germline, whereas no such effect was observed in female Ucp1-iCre mice. These findings suggest that Ucp1-iCre mice offer promising utility in the context of conditional gene manipulation in thermogenic adipose tissues, while also highlighting the need for caution in mouse mating and genotyping procedures.NEW & NOTEWORTHY Ucp1 promoter-driven Cre transgenic mice are useful in the manipulation of gene expression specifically in thermogenic adipose tissues. The widely used Ucp1-Cre mouse line (Ucp1-CreEvdr), which was generated using the bacterial artificial chromosome (BAC) strategy, exhibits major brown and white fat transcriptomic dysregulation and ectopic activity beyond adipose tissues. Here, we comprehensively validate Ucp1-iCre knockin mice, which serve as another optional model besides Ucp1-CreEvdr mice for specific genetic manipulation in thermogenic tissue.

Succinate activates UCP2 to suppress neuroinflammation and confer protection following intracerebral hemorrhage.

Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH. We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage.

Carbonic anhydrase 2 mediates anti-obesity effects of black tea as thermogenic activator

Obesity is a metabolic disorder due to over-accumulation of adipose tissue and ultimately becomes a “disease”. Brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning emerge as a potential strategy of anti-obesity by dissipating energy as heat. However, drugs based on adipose tissue thermogenesis have not been successfully approved yet. In current study, we found that black tea extract (BTE) obtained by patent-authorized manufacturing process prevented body weight gain as novel thermogenic activator with reduction of adiposity, improvement of adipose distribution, and glucose metabolism improvement in diet-induced obesity mice. Mechanismly, anti-obesity effect of BTE depends on promoting BAT thermogenesis and WAT browning with upregulation of uncoupling protein 1 (UCP1), especially visceral adipose tissue (VAT) with browning resistance. Specifically, utilizing in silico approach of network pharmacology and molecular docking, we identified carbonic anhydrase 2 (CA2) in nitrogen metabolism as anti-obesity target of BTE and further elucidated that protein kinase B (AKT) signaling pathway linked CA2 and UCP1. Meanwhile gut microbiota regulation may prompt the CA2-dependent thermogenesis activation. Our findings demonstrated anti-obesity effect of BTE as thermogenic activator through CA2-mediated BAT thermogenesis and WAT browning via CA2-AKT-UCP1 signaling pathway, which could be developed as promising anti-obesity agent with good safety and efficacy.

Research Progress on PGE and Retrograde Signaling Under Environmental Stress

Plastid gene expression (PGE) and retrograde signaling are pivotal processes in plant cellular function, particularly under environmental stress conditions. This literature review synthesizes current research on the role of PGE and retrograde signaling in plant stress responses. Environmental stresses such as drought, salinity, and extreme temperatures significantly alter PGE and trigger retrograde signaling pathways, which in turn modulate nuclear gene expression to maintain cellular homeostasis. Key insights include the identification of the GENOMES UNCOUPLED (GUN) proteins, especially GUN1, as crucial mediators that accumulate under stress and interact with plastid proteins to transmit signals to the nucleus. Technological advances in genomics, transcriptomics, and proteomics have provided comprehensive insights into these mechanisms, highlighting the dynamic nature of plant stress responses. Understanding these processes offers potential strategies for enhancing crop resilience through genetic engineering and other biotechnological interventions. This review underscores the importance of continued research in this field to improve crop productivity and sustainability under adverse environmental conditions.

Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity.

Warm-blooded animals such as birds and mammals are able to protect stable body temperature due to various thermogenic mechanisms. These processes can be facultative (occurring only under specific conditions, such as acute cold) and adaptive (adjusting their capacity according to long-term needs). They can represent a substantial part of overall energy expenditure and, therefore, affect energy balance. Classical mechanisms of facultative thermogenesis include shivering of skeletal muscles and (in mammals) non-shivering thermogenesis (NST) in brown adipose tissue (BAT), which depends on uncoupling protein 1 (UCP1). Existence of several alternative thermogenic mechanisms has been suggested. However, their relative contribution to overall heat production and the extent to which they are adaptive and facultative still needs to be better defined. Here we focus on comparison of NST in BAT with thermogenesis in skeletal muscles, including shivering and NST. We present indications that muscle NST may be adaptive but not facultative, unlike UCP1-dependent NST. Due to its slow regulation and low energy efficiency, reflecting in part the anatomical location, induction of muscle NST may counteract development of obesity more effectively than UCP1-dependent thermogenesis in BAT.

Huanglian-Jiedu decoction promotes adipose thermogenesis in obese mice by suppressing the expression of HDAC3

Ethnopharmacological relevanceHuanglian Jiedu Decoction (HLJDD) is an ancient formula of traditional Chinese medicine that is commonly utilized in a range of disorders, and it has been shown to have pharmacological effects on glucose and lipid metabolism. However, the specific mechanism of HLJDD for the treatment of obesity and related metabolic disorders remains to be further investigated. Aim of the studyIt has been thought that encouraging adipose thermogenesis to raise the body's energy expenditure is a useful tactic for improving metabolic abnormalities and losing weight. In this study, we investigated the ability and underlying mechanisms of HLJDD to regulate fat cell thermogenesis to improve energy expenditure in obesity. MethodsThe obese mouse model was established on a high-fat diet for 12 weeks. All mice were divided into NC, HFD, HFD with HLJDD of a low dose (2.25 g/kg/d), and HFD with HLJDD of a high dose (4.5 g/kg/d) groups and kept for 4 weeks. In vitro experiments were conducted to evaluate the effects of 5% and 10% HLJDD-containing serum on differentiated 3T3-L1 cells and HDAC3-knocking-down 3T3-L1 cells. ResultsThe results showed that HLJDD treatment significantly improved glucose and insulin tolerance and decreased the adipocyte radius of WATs, as well as increased energy consumption in obese mice. Besides, HLJDD treatment dramatically increased the levels of thermogenic genes UCP-1 and PGC-1α while suppressing HDAC3 levels in WATs and 3T3-L1 adipocytes. Importantly, the effects of HLJDD on PGC-1α and UCP-1 were blocked in HDAC3 knockdown adipocytes. ConclusionsTherefore, these results suggest that HLJDD enhanced adipose thermogenesis and improved energy expenditure by inhibiting HDAC3, thereby increasing UCP-1 and PGC-1α expression. These findings amplified the mechanisms of HLJDD and its potential to treat obesity and related metabolic disorders.

Resveratrol stimulates brown of white adipose via regulating ERK/DRP1-mediated mitochondrial fission and improves systemic glucose homeostasis.

Diabetes mellitus and metabolic homeostasis disorders may benefit from white adipose tissue (WAT) browning, which is associated with mitochondrial fission. Resveratrol, a dietary polyphenol, exhibits beneficial effects against abnormalities related to metabolic diseases. However, it remains unknown whether resveratrol contributes to WAT browning by regulating mitochondrial fission. We administered resveratrol (0.4% mixed with control) to db/db mice for 12 weeks, measuring body weight, oral glucose tolerance, insulin tolerance, and histological changes. The uncoupling protein 1 (UCP1) and dynamin-related protein 1 (DRP1) expressions in the epididymal WAT were assessed via immunoblotting. We found that resveratrol improved systemic glucose homeostasis and insulin resistance in db/db mice, which was associated with increased UCP1 in epididymal WAT. Resveratrol-treated mice exhibited more fragmented mitochondria and increased phosphorylation of DRP1 in the epididymal WAT of the db/db mice. These results were further confirmed in vitro, where resveratrol induced extracellular signal-regulated kinase (ERK) signaling activation, leading to phosphorylation of DRP1 at the S616 site (p-DRP1S616) and mitochondrial fission, which was reversed by an ERK inhibitor in 3T3-L1 adipocytes. Resveratrol plays a role in regulating the phosphorylation of ERK and DRP1, resulting in the promotion of beige cells with epididymal WAT and the improvement of glucose homeostasis. Our present study provides novel insights into the potential mechanism of resveratrol-mediated effects on WAT browning, suggesting that it is, at least in part, mediated through ERK/DRP1-mediated mitochondrial fission.

Nucleotide specificity of human uncoupling protein 1 inhibition

Nucleotide specificity of human uncoupling protein 1 inhibition

Chronic β3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.

GENOMES UNCOUPLED PROTEIN1 binds to plastid RNAs and promotes their maturation

Plastid biogenesis and the coordination of plastid and nuclear genome expression through anterograde and retrograde signaling are essential for plant development. GENOMES UNCOUPLED1 (GUN1) plays a central role in retrograde signaling during early plant development. The putative function of GUN1 has been extensively studied, but its molecular function remains controversial. Here, we evaluate published transcriptome data and generate our own data from gun1 mutants grown under signaling-relevant conditions to show that editing and splicing are not relevant for GUN1-dependent retrograde signaling. Our study of the plastid (post)transcriptome of gun1 seedlings with white and pale cotyledons demonstrates that GUN1 deficiency significantly alters the entire plastid transcriptome. By combining this result with a pentatricopeptide repeat code-based prediction and experimental validation by RNA immunoprecipitation experiments, we identified several putative targets of GUN1, including tRNAs and RNAs derived from ycf1.2, rpoC1, and rpoC2 and the ndhH–ndhA–ndhI–ndhG–ndhE–psaC–ndhD gene cluster. The absence of plastid rRNAs and the significant reduction of almost all plastid transcripts in white gun1 mutants account for the cotyledon phenotype. Our study provides evidence for RNA binding and maturation as the long-sought molecular function of GUN1 and resolves long-standing controversies. We anticipate that our findings will serve as a basis for subsequent studies on mechanisms of plastid gene expression and will help to elucidate the function of GUN1 in retrograde signaling.

Role of the sympathetic nervous system in cancer-associated cachexia and tumor progression in tumor-bearing BALB/c mice

BackgroundAdipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting.MethodsWe sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression.ResultsTumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group.ConclusionThe SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model.

TRPV1 Activation Antagonizes High-Fat Diet-Induced Obesity at Thermoneutrality and Enhances UCP-1 Transcription via PRDM-16.

Body weight is a balance between energy intake and energy expenditure. Energy expenditure is mainly governed by physical activity and adaptive thermogenesis. Adaptive dietary thermogenesis in brown and beige adipose tissue occurs through mitochondrial uncoupling protein (UCP-1). Laboratory mice, when housed at an ambient temperature of 22-24 °C, maintain their body temperature by dietary thermogenesis, eating more food compared to thermoneutrality. Humans remain in the thermoneutral zone (TNZ) without expending extra energy to maintain normal body temperature. TRPV1 activation by capsaicin (CAP) inhibited weight gain in mice housed at ambient temperature by activating UCP-1-dependent adaptive thermogenesis. Hence, we evaluated the effect of CAP feeding on WT and UCP-1-/- mice maintained under thermoneutral conditions. Our research presents novel findings that TRPV1 activation by CAP at thermoneutrality counters obesity in WT mice and promotes PRDM-16-dependent UCP-1 transcription. CAP fails to inhibit weight gain in UCP-1-/- mice housed at thermoneutrality and in adipose tissue-specific PRDM-16-/- mice. In vitro, capsaicin treatment increases UCP-1 transcription in PRDM-16 overexpressing cells. Our data indicate for the first time that TRPV1 activation counters obesity at thermoneutrality permissive for UCP-1 and the enhancement of PRDM-16 is not beneficial in the absence of UCP-1.

Natriuretic peptide receptor-C perturbs mitochondrial respiration in white adipose tissue

Natriuretic peptide receptor-C (NPR-C) is highly expressed in adipose tissues and regulates obesity-related diseases; however, the detailed mechanism remains unknown. In this research, we aimed to explore the potential role of NPR-C in cold exposure and high-fat/high-sugar (HF/HS) diet-induced metabolic changes, especially in regulating white adipose tissue (WAT) mitochondrial function. Our findings showed that NPR-C expression, especially in epididymal WAT (eWAT), was reduced after cold exposure. Global Npr3 (gene encoding NPR-C protein) deficiency led to reduced body weight, increased WAT browning, thermogenesis, and enhanced expression of genes related to mitochondrial biogenesis. RNA-sequencing of eWAT showed that Npr3 deficiency enhanced the expression of mitochondrial respiratory chain complex genes and promoted mitochondrial oxidative phosphorylation in response to cold exposure. In addition, Npr3 KO mice were able to resist obesity induced by HF/HS diet. Npr3 knockdown in stromal vascular fraction (SVF)-induced white adipocytes promoted the expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), uncoupling protein one (UCP1), and mitochondrial respiratory chain complexes. Mechanistically, NPR-C inhibited cGMP and calcium signaling in an NPR-B-dependent manner but suppressed cAMP signaling in an NPR-B-independent manner. Moreover, Npr3 knockdown induced browning via AKT and p38 pathway activation, which were attenuated by Npr2 knockdown. Importantly, treatment with the NPR-C-specific antagonist, AP-811, decreased WAT mass and increased PGC-1α, UCP1, and mitochondrial complex expression. Our findings reveal that NPR-C deficiency enhances mitochondrial function and energy expenditure in white adipose tissue, contributing to improved metabolic health and resistance to obesity.