Increased Energy Expenditure Research Articles

Paraventricular oxytocin neurons impact energy intake and expenditure: projections to the bed nucleus of the stria terminalis reduce sucrose consumption.

The part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves. Here we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (OxtPVH). We then identify a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis using the cell-selective expression of channel rhodopsin. OxtPVH neurons increase their expression of cFos after both physiological (fast-induced re-feeding or oral lipid) and pharmacological (systemic administration of cholecystokinin or lithium chloride) anorectic signals. Chemogenetic activation of OxtPVH neurons is sufficient to decrease free-feeding in Oxt Cre:hM3Dq mice, while inhibition in Oxt Cre:hM4Di mice attenuates the response to administration of cholecystokinin. Activation of OxtPVH neurons also increases energy expenditure and core-body temperature, without a significant effect on locomotor activity. Finally, the selective, optogenetic stimulation of a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis reduces the consumption of sucrose. Our results support a role for oxytocin neurons in the regulation of whole-body metabolism, including a modulatory action on food intake and energy expenditure. Furthermore, we demonstrate that the pathway from OxtPVH neurons to the bed nucleus of the stria terminalis can regulate sugar consumption.

Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.

Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.

Intestinal Stearoyl-CoA Desaturase-1 Regulates Energy Balance via Alterations in Bile Acid Homeostasis

Background and AimsStearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid assimilation and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance. MethodsTo interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine- specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analyses of bile acid content and composition, metabolic phenotyping including body composition, indirect calorimetry, glucose tolerance analyses, quantification of the composition of the gut microbiome, and assessment of bile acid signaling pathways. ResultsIKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt. In addition, the alpha and beta diversity of the gut microbiome was reduced in iKO mice, with several alterations in microbe species being associated with the observed increases in plasma bile acids. These increases in plasma bile acids were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and elevated plasma glucagon-like peptide-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice. ConclusionOur results indicate that deletion of intestinal SCD1 has significant impacts on bile acid homeostasis and whole-body energy balance, likely via activation of TGR5.

Abstract 41: SerpinA3N in Leptin Receptor Neurons Regulates Metabolic Homeostasis and Cardiovascular Function

Obesity and associated conditions such as type 2 diabetes are among the most concerning health issues in the U.S. Leptin receptor (LepR) signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. SerpinA3N is a serine protease inhibitor which is highly expressed in the arcuate nucleus of the hypothalamus, upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the LepR expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis confirmed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the LepR positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in LepR expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3N fl/fl ) with mice expressing Cre recombinase driven by the LepR (LepRb Cre ). We found that female, but not male, conditional knockout (CKO, LepRb Cre /SerpinA3N fl/fl ) mice have significantly lower body weight when fed HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response to leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but no change in insulin sensitivity. Insulin-induced phosphorylation of AKT was elevated only in skeletal muscleof CKO mice relative to controls. Finally, systolic arterial blood pressure of CKO mice fed HFHSD trend to be lower during dark time compared to controls (142±6.4 vs 127.9±7.1 mmHg, p=0.06), although heart rate was not changed. These results demonstrate that SerpinA3N in LepRb-expressing neurons regulate energy and glucose homeostasis in a sex-dependent manner,and may protect from HFHSD induced hypertension.

Murine nuclear tyrosyl-tRNA synthetase deficiency leads to fat storage deficiency and hearing loss

Aminoacyl-tRNA synthetases are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal, revealing its systemic impact on metabolism. Nuclear TyrRS deficiency (YarsΔNLS) led to reduced lean mass, reflecting a mild developmental defect, and reduced fat mass, possibly due to increased energy expenditure. Consistently, YarsΔNLS mice exhibit improved insulin sensitivity and reduced insulin levels, yet maintain normoglycemia, indicative of enhanced insulin action. Notably, YarsΔNLS mice also develop progressive hearing loss. These findings underscore the crucial function of nuclear TyrRS in the maintenance of fat storage and hearing and suggest that aminoacyl-tRNA synthetases' regulatory roles can affect metabolic pathways and tissue-specific health. This work broadens our understanding of how protein synthesis interconnects metabolic regulation to ensure energy efficiency.

Abstract P216: Distal Convoluted Tubule-Specific Deletion of Specific Deletion of (Pro)Renin Receptor in Mice Increases Energy Expenditure and Enhances Aggressiveness

Our previous study suggested a potential role of (pro)renin receptor (PRR) in the regulation of Na + -Cl - cotransporter (NCC) activity in the distal convoluted tubule (DCT). Here, we employed Slc12a3 -CreERT2 to generate inducible DCT-specific deletion of PRR in mice (KO). As expected, the KO mice exhibited a 1.8-fold increase in renal NCC activity as reflected by HCTZ-induced natriuresis. Surprisingly, the KO mice developed metabolic and behavioral phenotypes. By calorimetry, 4-month-old male KO mice exhibited an enhanced energy expenditure as compared with floxed controls (oxygen consumption: 4172.5 ± 118.0 ml/kg/hr vs. 3303.5 ± 69.8 ml/kg/hr; CO 2 consumption: 3617.3 ± 87.8 ml/kg/hr vs. 2784.2 ± 58.5 ml/kg/hr; heat production: 20.4 ± 0.6 Kcal/kg/h vs. 16.2 ± 0.8 Kcal/kg/h, n = 5-9, p < 0.01), accompanied by enhanced locomotor activity (by 41.3%) and reduced body weight (30.2 ± 0.5 g vs. 28.0 ± 0.3 g, n = 5-9, p < 0.05). The changes in locomotor activity were confirmed by using radiotelemetry. Additionally, resident-intruder aggression test demonstrated that under basal condition, the KO mice exhibited a higher aggression rate as compared with floxed controls (80% in KO group vs . 30% in floxed group, n = 10). The KO mice also exhibited shorter clinch attack latencies, higher number of attacks and attack duration (attack latencies: 79.0 ± 17.6 s in KO group vs . 172.5 ± 5.3 s in floxed group; attack frequency: 3.4 ± 0.8 in KO group vs . 0.7 ± 0.4 in floxed group; attack duration: 10.1 ± 2.0 s in KO group vs . 1.1 ± 0.6 s in floxed group, n = 10, p < 0.01). Furthermore, the KO mice exhibited elevated plasma level of Klotho (321.4 ± 16.3 pg/ml in KO group vs. 254.1 ± 9.8 pg/ml in floxed group, n = 11-12, p < 0.01) that is known to promote energy expenditure in addition to its cardiorenal protective actions. In cultured renal HK2 cells, recombinant soluble PRR (sPRR-His) downregulated Klotho mRNA and protein expression by 29.8% and 37.9%, respectively. Overall, the present study uncovered a novel role of DCT PRR in the regulation of energy metabolism and behavior, part of which may be mediated by antagonism of Klotho action.

Lower total cholesterol and triglyceride levels in ankylosing spondylitis than non-inflammatory rheumatic disease controls in a 1978-98 study: a potential effect of increased physical energetics in manual occupations in the pre-2000 chronologic era.

No article on serum lipids in ankylosing spondylitis (AS) and control subjects has been reported from USA. The primary aim of this study was to determine if any difference occurred in serum lipid levels in AS and control rheumatic disorders in two time periods, 1978-98 and 2000-10. The secondary aim was to investigate variables associated with lipid levels and if a difference was found between AS and control disorders. The AS patients were compared to non-inflammatory rheumatic disorders (NIRDs) in 1978-98 and 2000-10 surveys and to rheumatoid arthritis (RA) in the 2000-10 survey. Patients were matched within 5 years of age, sex, and clinic or hospital source. In the 1978-98 survey, entry mean (SEM) serum cholesterol level [mg/dL] was highly (p<0.001) significantly lower in 69 AS [179.0 (4.8)] than 69 matched NIRD controls [208.0 (5.6)]. In 29 pairs of AS and NIRD subjects having manual labour occupations, mean (SEM) cholesterol level was additionally lower in AS [156.7 (5.9)] and higher in 29 NIRD controls [213.3 (8.6)] (p<0.001). In manual labour workers, mean (SEM) serum triglyceride was significantly lower (p=0.004) in 15 AS [110.3 (14.1)] than 14 NIRD controls [185.2 (19.3)]. In the 2000-10 survey, no lipid difference was found between AS vs. NIRD control patients. In the 1978-98 survey, AS had significantly lower mean serum cholesterol and triglyceride levels than NIRD control patients. Associated manual labour occupations may have significantly contributed to results, possibly related to increased energy expenditures from physical activity in the pre-2000 era.

Triple jeopardy: The combined effects of viral, chemical, and thermal stress on kuruma prawn (Penaeus japonicus) juveniles

Growing concerns have emerged over the combined effects of multiple stressors on ecosystems. Empirical evidence shows that the sensitivity of aquatic invertebrates to insecticides varies under thermally fluctuating conditions. Additionally, field surveys in estuarine areas of western Japan confirmed the presence of juvenile kuruma prawns (Penaeus japonicus) carrying the white spot syndrome virus (WSSV). Given the potential of co-exposure to multiple stressors, we performed a combined exposure experiment using a full-factorial design with three stressors: WSSV infection (presence or absence: initial 2 h exposure), fipronil (insecticide) exposure (0 or 0.1 μg/L: 14 d exposure), and temperature (20, 25, or 30 °C). We observed the highest mortality (75 %) in the WSSV + Fipronil treatment at 30 °C, with the associated specimens showing significant changes in the internal load of WSSV and concentrations of fipronil and its metabolite, fipronil sulfone. Severe perturbations of metabolites associated with increased energy expenditure and fatty acid utilization have been identified as potential factors underlying lethality in juvenile kuruma prawns. The results demonstrate that WSSV infection increases the susceptibility of thermally stressed juvenile kuruma prawns to fipronil. Therefore, further studies are required to determine the combined effects of multiple stressors in environmentally relevant scenarios on juvenile kuruma prawns as well as in estuarine ecosystems.

Cold-induced phosphatidylethanolamine synthesis in liver and brown adipose tissue of mice

Increasing energy expenditure in brown adipose (BAT) tissue by cold-induced lipolysis is discussed as a potential strategy to counteract imbalanced lipid homeostasis caused through unhealthy lifestyle and cardiometabolic disease. Yet, it is largely unclear how liberated fatty acids (FA) are metabolized. We investigated the liver and BAT lipidome of mice housed for 1 week at thermoneutrality, 23 °C and 4 °C using quantitative mass spectrometry-based lipidomics. Housing at temperatures below thermoneutrality triggered the generation of phosphatidylethanolamine (PE) in both tissues. Particularly, the concentrations of PE containing polyunsaturated fatty acids (PUFA) in their acyl chains like PE 18:0_20:4 were increased at cold. Investigation of the plasma's FA profile using gas chromatography coupled to mass spectrometry revealed a negative correlation of PUFA with unsaturated PE in liver and BAT indicating a flux of FA from the circulation into these tissues. Beta-adrenergic stimulation elevated intracellular levels of PE 38:4 and PE 40:6 in beige wildtype adipocytes, but not in adipose triglyceride lipase (ATGL)-deficient cells. These results imply an induction of PE synthesis in liver, BAT and thermogenic adipocytes after activation of the beta-adrenergic signaling cascade.

Inhibition of Thyroid Hormone Signaling in the Zona Incerta Alters Basal Metabolic Rate, Behavior, and Serum Glucocorticoids in Male Mice.

Background: It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. Results: Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. Conclusions: Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses.

Nutritional Assessment in Outpatients with Heart Failure.

Heart failure (HF) is associated with significant alterations in body composition, including malnutrition due to insufficient intake, chronic inflammation and increased energy expenditure. Identifying the prevalence of malnutrition and the risk of sarcopenia in patients with HF is crucial to improve clinical outcomes. This cross-sectional, single-center, observational study involved 121 outpatients diagnosed with HF. Nutritional status was assessed using the Mini Nutritional Assessment (MNA), the Malnutrition Universal Screening Tool (MUST), and the Subjective Global Rating (SGA). Sarcopenia was screened using the SARC-F (Strength, Assistance in walking, Rise from a chair, Climb stairs, Falls) questionnaire and diagnosed based on the European Working Group in Older People (EWGSOP2) criteria and functionality with the Short Performance Battery (SPPB) test. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria. The study found that 10.7% had cardiac cachexia and 45.4% of deceased patients had been in this condition (p = 0.002). Moderate-to-high risk of malnutrition was identified in 37.1%, 23.9%, and 31.4% of patients according to the MNA, MUST, and SGA tests, respectively. According to the GLIM criteria, 56.2% of patients were malnourished. Additionally, 24.8% of patients had a high probability of sarcopenia, and 57.8% were not autonomous according to SPPB. Patients with less than 30% quadriceps muscle contraction were at a high risk of sarcopenia. There is a high prevalence of malnutrition among outpatients with HF, which is associated with worse prognosis, increased risk of sarcopenia, and greater frailty. These findings underscore the importance of early nutritional and functional assessments in this population to improve clinical outcomes.

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.

SiRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice

Atherosclerotic cardiovascular disease is closely correlated with elevated low density lipoprotein-cholesterol. In feeding state, glucose and insulin activate mammalian target of rapamycin 1 that phosphorylates the deubiquitylase ubiquitin-specific peptidase 20 (USP20). USP20 then stabilizes HMG-CoA reductase, thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity, and increased energy expenditure through elevating UCP1. In Ldlr−/− mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

Leptin Activation of Dorsal Raphe Neurons Inhibits Feeding Behavior.

Leptin is a homeostatic regulatory element that signals the presence of adipocyte energy stores, reduces food intake, and increases energy expenditure. Similarly, serotonin (5- HT), a signaling molecule found in both the central and peripheral nervous systems, also controls food intake. Using neuronal tract-tracing, pharmacological and optogenetics approaches, and in vivo microdialysis, combined with behavioral endpoints, we tested the hypothesis that leptin controls food intake not only by activating hypothalamic leptin receptors (LepRs), but also through activation of LepRs expressed by serotonergic raphe neurons that send projections to the arcuate (ARC). We show that microinjection of leptin directly into the dorsal raphe nucleus (DRN) reduces food intake in rats. This effect is mediated by LepR expressing neurons in the DRN as selective optogenetic activation of these neurons at either their DRN cell bodies or their ARC terminals reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing LepRs that send projections to the ARC. Finally, by utilizing in vivo microdialysis, we show that leptin administration to the DRN increases 5-HT efflux into the ARC, and specific antagonism of the 5-HT2C receptors in the ARC diminishes the leptin anorectic effect. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, identifying a new level of interaction between leptin and serotonin to control food intake. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders.

Embryonic Lethal Phenotyping to Identify Candidate Genes Related with Birth Defects.

Congenital birth defects contribute significantly to preterm birth, stillbirth, perinatal death, infant mortality, and adult disability. As a first step to exploring the mechanisms underlying this major clinical challenge, we analyzed the embryonic phenotypes of lethal strains generated by random mutagenesis. In this study, we report the gross embryonic and perinatal phenotypes of 55 lethal strains randomly picked from a collection of mutants that carry piggyBac (PB) transposon inserts. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested most of the analyzed mutations hit genes involved in heart and nervous development, or in Notch and Wnt signaling. Among them, 12 loci are known to be associated with human diseases. We confirmed 53 strains as embryonic or perinatal lethal, while others were subviable. Gross morphological phenotypes such as body size abnormality (29/55, 52.73%), growth or developmental delay (35/55, 63.64%), brain defects (9/55, 16.36%), vascular/heart development (31/55, 56.36%), and other structural defects (9/55, 16.36%) could be easily observed in the mutants, while three strains showed phenotypes similar to those of human patients. Furthermore, we detected body weight or body composition alterations in the heterozygotes of eight strains. One of them was the TGF-β signaling gene Smad2. The heterozygotes showed increased energy expenditure and a lower fat-to-body weight ratio compared to wild-type mice. This study provided new insights into mammalian embryonic development and will help understand the pathology of congenital birth defects in humans. In addition, it expanded our understanding of the etiology of obesity.

Malnutrition in Amyotrophic Lateral Sclerosis: Insights from Morphofunctional Assessment and Global Leadership Initiative on Malnutrition Criteria.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease frequently accompanied by malnutrition due to weight loss, increased energy expenditure, and muscle mass loss. This study aimed to evaluate morphofunctional assessment tools as predictors of malnutrition and to investigate their relationship with muscle status and disease severity in ALS patients. A cross-sectional study was conducted with 45 ALS patients at the San Cecilio University Hospital in Granada. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional assessment was performed using Bioimpedance Vectorial Analysis (BIVA), handgrip strength (HGS), and Short Physical Performance Battery (SPPB). Malnutrition prevalence was 38% according to GLIM criteria. Significant differences were observed between malnourished and non-malnourished groups in age (70 ± 9 vs. 62 ± 10 years, p = 0.01), sex (female prevalence: 58.8% vs. 25.0%, p = 0.02), dysphagia prevalence (83% vs. 29%, p < 0.001), PEG/PRG use (35.3% vs. 3.6%, p = 0.01), and ALSFRS-R scores (30 ± 12 vs. 34 ± 12, p = 0.02). Malnourished patients had lower values in anthropometric measurements, muscle mass obtained by BIVA, and phase angle (PA) (4.05 ± 0.8° vs. 5.09 ± 0.8°, p < 0.001). No significant differences were found in muscle strength or functional status. PA showed significant correlations with muscle strength (r = 0.52, p < 0.001) and muscle mass measures (r = 0.48, p < 0.001). Moreover, PA was associated with poorer disease progression and physical performance. In our sample, BIVA metrics such as PA (<4.3°), SPA (<-0.8), body cell mass (<9.2 kg/m), and extracellular water (>49.75%) were identified as malnutrition risk factors. The study underscores the critical importance of comprehensive morphofunctional assessment and the use of advanced diagnostic criteria, for early identification and intervention in malnutrition among people with ALS. Further research is warranted to validate these findings and develop targeted nutritional strategies into routine clinical practice.

Swimming in cold water increases the browning process by diminishing the Myostatin pathway

BackgroundBrown adipose tissue (BAT) is a thermogenic tissue that uncouples oxidative phosphorylation from ATP synthesis and increases energy expenditure via non-shivering thermogenesis in mammals. Cold exposure and exercise have been shown to increase BAT and browning of white adipose tissue (WAT) in mice. This study aimed to determine whether there is an additive effect of exercise during cold exposure on markers related to browning of adipose tissue. in Wistar rats.MethodsTwenty-four male Wistar rats were randomly divided into three groups: Control (C, 25˚C), Swimming in Neutral (SN, 30˚C) water, and Swimming in Cold (SC, 15˚C) water. Swimming included intervals of 2–3 min, 1 min rest, until exhausted, three days a week for six weeks, with a training load of 3–6% body weight. After the experimental protocol, interscapular BAT and inguinal subcutaneous white adipose tissue (WAT) were excised, weighed, and processed for beiging marker gene expression.ResultsSN and SC resulted in lower body weight gain, associated with reduced WAT and BAT volume and increased BAT number with greater effects observed in SC. Myostatin protein expression was lower in BAT, WAT, soleus muscle, and serum NC and SC compared to the C group. Expression of the interferon regulatory factor-4 (IRF4) gene in both BAT and WAT tissues was significantly greater in the SC than in the C. Expression of the PGC-1α in BAT was significantly increased in the SC compared to C and increased in WAT in NC and SC. Expression of the UCP1 in BAT and WAT increased in the SC group compared to other groups.ConclusionThe findings demonstrate that six weeks of swimming training in cold water promotes additive effects of the expression of genes and proteins involved in the browning process of adipose tissue in Wistar rats. Myostatin inhibition may possess a regulator effect on the PGC-1α – UCP1 pathway that mediates adipose tissue browning.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

5-Methoxy-2-aminoindane Reverses Diet-Induced Obesity and Improves Metabolic Parameters in Mice: A Potential New Class of Antiobesity Therapeutics.

The escalating prevalence of obesity and its related disorders represents a daunting global health challenge. Unfortunately, current pharmacological interventions for obesity remain limited and are often associated with debilitating side effects. Against this backdrop, the psychoactive aminoindane derivative 5-methoxy-2-aminoindane (MEAI) has gained considerable attention for its ability to induce a pleasurable, alcohol-like sensation while curbing alcohol consumption. Given the potential impact of MEAI on food addiction and energy homeostasis, we examined its metabolic efficacy on appetite regulation, obesity, and related comorbidities under acute and chronic settings, utilizing a mouse model of diet-induced obesity (DIO). Our results demonstrated that MEAI treatment significantly reduced DIO-induced overweight and adiposity by preserving lean mass and decreasing fat mass. Additionally, MEAI treatment exhibited positive effects on glycemic control by attenuating DIO-induced hyperglycemia, glucose intolerance, and hyperinsulinemia. Furthermore, MEAI reduced DIO-induced hepatic steatosis by decreasing hepatic lipid accumulation and lowering liver triglyceride and cholesterol levels, primarily by inhibiting de novo lipid synthesis. Metabolic phenotyping revealed that MEAI increased energy expenditure and fat utilization while maintaining food consumption similar to that of the vehicle-treated group. Lastly, MEAI normalized voluntary locomotion actions without any overstimulatory effects. These findings provide compelling evidence for the antiobesity effects of MEAI treatment and call for further preclinical testing. In conclusion, our study highlights the potential of MEAI as a novel therapeutic approach for treating obesity and its associated metabolic disorders, offering hope for the development of new treatment options for this global health challenge.

Sestrin2 in POMC neurons modulates energy balance and obesity related metabolic disorders via mTOR signaling

Sestrin2 is a highly conserved protein that can be induced under various stress conditions. Researches have revealed that the signaling pathway of the mammalian target of rapamycin (mTOR) is essential in modulating both glucose and lipid metabolism. However, the precise involvement of Sestrin2 in the hypothalamus, particularly in pro-opiomelanocortin (POMC) neurons, in control of energy homeostasis remains uncertain. In this study, we aimed to investigate the functional role of Sestrin2 in hypothalamic POMC neurons in regulation of energy balance, as well as revealing the underlying mechanisms. Therefore, cre-dependent AAV virus encoding or silencing Sestrin2 was injected into the hypothalamic ARC of pomc-cre transgenic mice. The results demonstrated that Sestrin2 overexpression in POMC neurons ameliorated high-fat diet (HFD)-induced obesity and increased energy expenditure. Conversely, Sestrin2 deficiency in POMC neurons predisposed mice to HFD induced obesity. Additionally, the thermogenesis of brown adipose tissue and lipolysis of inguinal white adipose tissue were both enhanced by the increased sympathetic nerve innervation in Sestrin2 overexpressed mice. Further exploration revealed that Sestrin2 overexpression inhibited the mTOR signaling pathway in hypothalamic POMC neurons, which may account for the alleviation of systematic metabolic disturbance induced by HFD in these mice. Collectively, our findings demonstrate that Sestrin2 in POMC neurons plays a pivotal role in maintaining energy balance in a context of HFD-induced obesity by inhibiting the mTOR pathway, providing new insights into how hypothalamic neurons respond to nutritional signals to protect against obesity-associated metabolic dysfunction.