Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation.

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis.

Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.

Psychological Distress in Young Chilean Adults Exposed to Parental Alienating Behaviors during Childhood/Adolescence.

The aim of this study was to analyze the psychological distress of young adults exposed to alienating behaviors during childhood/adolescence. Four hundred and sixteen adults responded to the online survey. A brief sociodemographic questionnaire, the Brief Symptom Scale, and a questionnaire on adverse childhood experiences were included. The analyses revealed that individuals who experienced one or more alienating behaviors exhibited higher levels of anxiety, depression, somatization, and overall psychological distress. Furthermore, even after controlling for the effect of other adverse childhood experiences, alienating behaviors had a significant impact on psychological distress in adulthood. This highlights an understudied aspect of alienating behaviors, i.e., their conjunction or parallelism with other adverse childhood experiences.

Exercise training modifies xenometabolites in gut and circulation of lean and obese adults.

Regular, moderate exercise modifies the gut microbiome and contributes to human metabolic and immune health. The microbiome may exert influence on host physiology through the microbial production and modification of metabolites (xenometabolites); however, this has not been extensively explored. We hypothesized that 6 weeks of supervised, aerobic exercise 3×/week (60%-75% heart rate reserve [HRR], 30-60 min) in previously sedentary, lean (n = 14) and obese (n = 10) adults would modify both the fecal and serum xenometabolome. Serum and fecal samples were collected pre- and post-6 week intervention and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Linear mixed models (LMMs) identified multiple fecal and serum xenometabolites responsive to exercise training. Further cluster and pathway analysis revealed that the most prominent xenometabolic shifts occurred within aromatic amino acid (ArAA) metabolic pathways. Fecal and serum ArAA derivatives correlated with body composition (lean mass), markers of insulin sensitivity (insulin, HOMA-IR) and cardiorespiratory fitness ( V ̇ O 2 max $$ \dot{\mathrm{V}}{\mathrm{O}}_{2\max } $$ ), both at baseline and in response to exercise training. Two serum aromatic microbial-derived amino acid metabolites that were upregulated following the exercise intervention, indole-3-lactic acid (ILA: fold change: 1.2, FDR p < 0.05) and 4-hydroxyphenyllactic acid (4-HPLA: fold change: 1.3, FDR p < 0.05), share metabolic pathways within the microbiota and were associated with body composition and markers of insulin sensitivity at baseline and in response to training. These data provide evidence of physiologically relevant shifts in microbial metabolism that occur in response to exercise training, and reinforce the view that host metabolic health influences gut microbiota population and function. Future studies should consider the microbiome and xenometabolome when investigating the health benefits of exercise.

Accesibilidad en la atención primaria de salud desde la perspectiva de migrantes y personal de salud en antofagasta, chile

Objetivo: Analizar los discursos y experiencias sobre la percepción de la accesibilidad a la atención primaria de salud desde la perspectiva de personas migrantes internacionales y el personal de salud en Antofagasta, zona norte de Chile. Material y Método: Estudio con enfoque cualitativo y diseño de tipo fenomenológico descriptivo; participaron 14 residentes de la comuna de Antofagasta durante el 2021, siete migrantes internacionales y 7 trabajadores de la atención primaria de salud. El muestreo fue no probabilístico por bola de nieve y la selección se realizó mediante participantes semilla. Resultados: Las categorías que presentan las personas migrantes son: 1) Accesibilidad Horaria, con subdimensiones: elementos del sistema y elementos del usuario; 2) Peligros Percibidos; 3) Discriminación, con subdimensiones: trato al usuario y disponibilidad de servicios; 4) Accesibilidad a la Información. Desde el personal de salud las categorías fueron: 1) Accesibilidad Horaria; 2) Peligros Percibidos; 3) Facilitadores en Salud. Conclusión: Existe una brecha entre la población migrante y el personal de salud, que no permite una óptima atención y accesibilidad, esto por la ausencia de capacitación, limitación de recursos y concientización.

Objective: To analyze the discourses and experiences regarding the perception of accessibility to primary healthcare from the perspective of international migrants and healthcare professionals in Antofagasta, northern Chile. Material and Method: A qualitative approach study with a descriptive phenomenological design, the sample consisted of 14 participants from the city of Antofagasta in the year 2021: 7 international migrants and 7 primary healthcare professionals. Non-probability sampling was used. The snowball method was used to select participants through seed participants. Results: The categories expressed by the migrants were: 1) Timely accessibility with the sub-dimensions: system elements and user elements; 2) Perceived hazards; 3) Discrimination with the sub-dimensions: user service and availability of services; 4) Information availability. From the health professionals' perspective, the categories were: 1) Timely accessibility; 2) Perceived hazards; 3) Health facilitators. Conclusion: There is a gap between the migrant population and healthcare professionals, which hinders optimal care and accessibility. This is attributed to lack of training, limited resources and awareness.

Objetivo: Analisar os discursos e experiências sobre a percepção da acessibilidade aos cuidados de saúde primários, do ponto de vista de pessoas migrantes internacionais e profissionais de saúde, em Antofagasta, região norte do Chile. Material e Método: Estudo com uma abordagem qualitativa e desenho fenomenológico descritivo. 14 residentes na cidade de Antofagasta participaram durante o ano de 2021: 7 migrantes internacionais e 7 profissionais de saúde primária. O tipo de amostra foi não probabilístico e a amostragem foi feita com o método bola de neve e a seleção foi conduzida por participantes semente. Resultados: As categorias apresentadas pelos migrantes são: 1) Acessibilidade horária, com as subdimensões: elementos do sistema e elementos do usuário; 2) Perigos percebidos; 3) Discriminação, com as subdimensões: tratamento do usuário e disponibilidade de serviços; 4) Acessibilidade de informações. Para os profissionais de saúde, as categorias foram: 1) Acessibilidade horária; 2) Perigos percebidos; 3) Facilitadores de saúde. Conclusão: Existe uma lacuna entre a população migrante e os profissionais de saúde que não permite uma atenção e acessibilidade ótimas, devido à falta de formação, limitações de recursos e conscientização.

Victimization by Caregivers: Prevalence and Risk Factors in Chilean Children and Adolescents.

This study examined the prevalence and risk factors associated to victimization by caregivers in a national large sample of Chilean children and adolescents. 19,687 children and adolescents aged 12-17, selected by random probability sampling of 699 public schools in Chile who were surveyed by trained interviewers. Victimization by Caregivers was evaluated through a module of the Juvenile Victimization Questionnaire (JVQ). The prevalence (12 months) for physical abuse were (12.9%), for emotional abuse (27.9%), neglect (5.3%) and parental interference (3.5%). The results suggest as risk factors, sex, age, migration status, disability, geographical location, and type of school. The findings highlight the urgent need to address the issue of child maltreatment and victimization by caregivers in Chilean society and minimize its impact.

Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated. Here, male and female breeders were fed a high-fat diet and housed with or without running wheels before breeding (males) and before and during gestation (females). Offspring were sedentary and chow fed, with parents as follows: sedentary (Sed), maternal exercise (MatEx), paternal exercise (PatEx), or maternal+paternal exercise (Mat+PatEx). Adult offspring from all parental exercise groups had similar improvement in glucose tolerance and hepatic glucose production. Targeted metabolomics was performed in offspring serum, liver, and triceps muscle. Offspring from MatEx, PatEx, and Mat+PatEx each had a unique tissue metabolite signature, but Mat+PatEx offspring had an additive phenotype relative to MatEx or PatEx alone in a subset of liver and muscle metabolites. Tissue metabolites consistently indicated that the metabolites altered with parental exercise contribute to enhanced fatty acid oxidation. These data identify distinct tissue-specific adaptations and mechanisms for parental exercise-induced improvement in offspring metabolic health. Further mining of this data set could aid the development of novel therapeutic targets to combat metabolic diseases.

Consumption of cricket (Acheta domesticus) flour decreases insulin resistance and fat accumulation in rats fed with high-fat and -fructose diet.

The consumption of cricket (Acheta domesticus, AD) has recently increased due to its high nutritional and bioactive compound contents. However, limited studies have explored the beneficial effects of AD consumption. Therefore, we aimed to evaluate the protective effect of a diet supplemented with AD flour on obesity control and its complications in an in vivo model. The chemical profiling of the AD showed an important protein content, chitin, and polyunsaturated fatty acids contents. For the in vivo study, a high-fructose and saturated fat diet (HFFD) was supplemented with AD (4% and 8%). The 8% AD supplementation reduced body weight gain (19%) and serum triglycerides (37%) in HFFD-fed rats. These benefits were related to a greater lipid excretion in feces (97%) and the partial inhibition of pancreatic lipase in vitro by the aqueous extract and the hydrolyzed proteins obtained from AD. Additionally, the 8% AD supplementation improved insulin resistance measured by the HOMA index (61%). Thus, 8% AD supplementation to HFFD-fed rats was effective in preventing obesity, dyslipidemia, and insulin resistance. PRACTICAL APPLICATIONS: Obesity is a risk factor for developing insulin resistance and dyslipidemia. Therefore, there is an increasing interest in consuming foods rich in bioactive compounds as therapeutic alternatives for managing the development of obesity and its complications. Edible insects, such as crickets, are attractive for treating obesity due to their content of protein, fiber, and polyunsaturated fatty acids. Studies have explored the effect of glycosaminoglycan (GAG)-enriched extracts from the cricket Gryllus bimaculatus against obesity. However, GAG content in crickets is low, and crickets are commonly consumed whole instead of extracts. The cricket Acheta domesticus (AD) is among the most rearing cricket species as it is easy to farm and has a better flavor. However, limited studies have explored the beneficial effects of AD consumption. This study demonstrates that AD prevents obesity and ameliorates dyslipidemia and insulin resistance. Therefore, AD is a valuable entomotherapeutic strategy to reduce the comorbidities associated with diet-induced obesity.

Prevalence and Risk Factors Associated with Mental Health in Adolescents from Northern Chile in the Context of the COVID-19 Pandemic.

The COVID-19 pandemic has affected the world population; however, there is limited knowledge about its impact on adolescents. The aim of this study was to estimate the prevalence and risk factors associated with mental health in the context of the COVID-19 pandemic in young people in northern Chile. The sample consisted of 1315 young people between the ages of 14 and 18. Univariate analysis and multiple logistic regression were performed to identify the risk factors associated to the considered symptomatology. Depressive symptomatology was reported at 36.3%, anxiety at 6%, and social phobia at 27.8%. Adolescent females reported a higher probability of presenting depressive (OR, 3.409), anxious (OR, 3.949), and social phobia (OR, 3.027) symptomatology. Young women between the ages of 17 and 18 were more likely to present anxiety (OR, 2.172); moreover, being a migrant was related to lower odds of presenting anxiety (OR, 0.259) and depression (OR, 0.662). Having a family member diagnosed with COVID-19 was associated with depressive symptomatology (OR, 1.369). The COVID-19 pandemic can have serious repercussions on the mental health of adolescents. It is important to generate interventions to meet the needs of youth during the post-confinement period.

Brown adipose tissue prevents glucose intolerance and cardiac remodeling in high-fat-fed mice after a mild myocardial infarction.

BACKGROUND: Obesity increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (T2D) after myocardial infarction (MI). Brown adipose tissue (BAT) is important to combat obesity and T2D, and increasing BAT mass by transplantation improves glucose metabolism and cardiac function. The objective of this study was to determine if BAT had a protective effect on glucose tolerance and cardiac function in high-fat diet (HFD) fed mice subjected to a mild MI. METHODS: Male C57BL/6 mice were fed a HFD for eight weeks and then divided into Sham (Sham-operated) and +BAT (mice receiving 0.1 g BAT into their visceral cavity). Sixteen weeks post-transplantation, mice were further subdivided into ±MI (Sham; Sham-MI; +BAT; +BAT-MI) and maintained on a HFD. Cardiac (echocardiography) and metabolic function (glucose and insulin tolerance tests, body composition and exercise tolerance) were assessed throughout 22 weeks post-MI. Quantitative PCR (qPCR) was performed to determine the expression of genes related to metabolic function of perigonadal adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), liver, heart, tibialis anterior skeletal muscle (TA); and BAT. RESULTS: +BAT prevented the increase in left ventricle mass (LVM) and exercise intolerance in response to MI. Similar to what is observed in humans, Sham-MI mice developed IGT post-MI, but this was negated in +BAT-MI mice. IGT was independent of changes in body composition. Genes involved in inflammation, insulin resistance, and metabolism were significantly altered in pgWAT, scWAT, and liver in Sham-MI mice compared to all other groups. CONCLUSIONS: BAT transplantation prevents IGT, the increase in LVM, and exercise intolerance following MI. MI alters the expression of several metabolic-related genes in WAT and liver in Sham-MI mice, suggesting that these tissues may contribute to the impaired metabolic response. Increasing BAT may be an important intervention to prevent the development of IGT or T2D and cardiac remodeling in obese patients post-MI.

Perspectivas y tendencias actuales del concepto de alienación parental: una revisión sistemática de la literatura / Current perspectives and trends of the concept of parental alienation: a systematic review of the literature

Resumen: Antecedentes: Son diversos las/os investigadoras/es que se han interesado por el fenómeno de la alienación parental. No obstante, esta compleja dinámica relacional no ha estado exenta de controversias. Objetivo: Realizar una revisión sistemática de las perspectivas y tendencias actuales del concepto de alienación parental, sus características y efectos en la población que experimentan estas circunstancias. Método: Se utilizó la metodología PRISMA-P para llevar a cabo una búsqueda bibliográfica exhaustiva de artículos publicados entre el año 2016 y junio de 2020 en revistas indexadas Scopus y/o WOS. Se contemplaron 95 estudios, de los cuales 11 fueron considerados para la revisión, de acuerdo con los criterios de inclusión y exclusión preestablecidos. Se identificó un amplio campo investigativo en el cual se circunscribe la alienación parental, como dinámica relacional. Resultados: Los 11 estudios seleccionados establecían relaciones entre la experiencia de alienación parental e indicadores de salud mental, tanto en niños, niñas, adolescentes, como adultos que experimentan o experimentaron estas dinámicas. Así también, se relacionó con maltrato psicológico. Conclusiones: La alienación parental es un fenómeno con una importante prevalencia en la población y se ha vinculado con un deterioro en la salud mental de las personas que la experimentan o la han experimentado.

Abstract: Background: Several researchers have been interested in the phenomenon of parental alienation. However, this complex relational dynamic has not been without controversy. Objective: To conduct a systematic review of current perspectives and trends on the concept of parental alienation, its characteristics and effects on the population experiencing these circumstances. Method: PRISMA-P methodology was used to conduct an exhaustive literature search of articles published between 2016 and June 2020 in Scopus and/or WOS indexed journals. Ninety-five studies were contemplated, of which 11 were considered for the review, according to the pre-established inclusion and exclusion criteria. A broad field of research was identified in which parental alienation is circumscribed as a relational dynamic. Results: The 11 selected studies established relationships between the experience of parental alienation and mental health indicators, both in children, adolescents and adults who experience or have experienced these dynamics. Thus, it was also related to psychological maltreatment. Conclusions: Parental alienation is a phenomenon with a significant prevalence in the population and has been linked to a deterioration in the mental health of people who experience or have experienced it.

Wearable Wireless Body Area Networks for Medical Applications.

In recent times, there has been a significant growth in networks known as the wireless body area networks (WBANs). A WBAN connects distributed nodes throughout the human body, which can be placed on the skin, under the skin, or on clothing and can use the human body's electromagnetic waves. An approach to reduce the size of different telecommunication equipment is constantly being sought; this allows these devices to be closer to the body or even glued and embedded within the skin without making the user feel uncomfortable or posing as a danger for the user. These networks promise new medical applications; however, these are always based on the freedom of movement and the comfort they offer. Among the advantages of these networks is that they can significantly increase user's quality of life. For example, a person can carry a WBAN with built-in sensors that calculate the user's heart rate at any given time and send these data over the internet to user's doctor. This study provides a systematic review of WBAN, describing the applications and trends that have been developed with this type of network and, in addition, the protocols and standards that must be considered.

Caloric restriction following early-life high fat-diet feeding represses skeletal muscle TNF in male rats.

Chronic metabolic diseases are on the rise worldwide and their etiology is multifactorial. Among them, inflammatory components like Tumor Necrosis Factor (TNF), contribute to whole-body metabolic impairment. Caloric Restriction (CR) combats metabolic diseases, but how it reduces inflammation remains understudied. We aimed to evaluate the impact of chronic CR on muscle inflammation, in particular TNF. In our study, 4-week old male Sprague-Dawley rats were fed a high-fat diet (HF, 45% Kcal of fat from lard) ad libitum for 3 months. After estimation of their energy requirement (1 month), they were then divided into three groups: HF ad libitum (OL), weight maintenance with AIN93M (9.5% Kcal from fat; ML, 100% of energy requirement), and caloric restriction (CR, AIN93M with 75% of energy requirement). This dietary intervention continued for six months. At this point, rats were sacrificed and gastrocnemius muscle was collected. CR induced a profound shift in fat and lean mass, and decreased growth factor IGF-1. Muscle qPCR analysis showed a marked decrease in inflammation and TNF (premRNA, mRNA, and protein) by CR, accompanied by Tnf promoter DNA hypermethylation. CR increased expression of histone deacetylase Sirt6 and decreased methyltransferase Suv39h1, together with decreased Tnf promoter and coding region binding of NF- κB and C/EBP-ß. Following miRNA database mining, qPCR analysis revealed that CR downregulated the proinflammatory miR-19b and increased the anti-inflammatory miR-181a and its known targets. Chronic CR is able to regulate muscle-specific inflammation by targeting the NF-κB pathway as well as transcriptional and post-transcriptional regulation of Tnf gene.

Weight loss with exercise improves muscle architecture and progenitor cell populations compared with weight loss alone in mice with preneoplastic colorectal lesions.

Weight loss and exercise reduce colorectal cancer (CRC) risk in persons with obesity. Whether weight loss and exercise effect myofiber characteristics and muscle stem/progenitor cell populations in mice with preneoplastic colorectal lesions, a model of CRC risk, is unknown. To address this gap, male C57Bl/6J mice were fed a high-fat diet (HFD) to induce obesity or a control (CON) diet prior to azoxymethane injection to induce preneoplastic colorectal lesions. The HFD group was then randomized to weight loss conditions that included (1) switching to the CON diet only (HFD-SED) or switching to the CON diet with treadmill exercise training (HFD-EX). Average myofiber cross-sectional area was not different between groups. There were more smaller-sized fibres in HFD-EX (p < 0.05 vs. CON), and more fibrosis in HFD-SED (p < 0.05 vs. HFD-EX and CON). There was a trend for more committed (Pax7+MyoD+) myoblasts (p = 0.059) and more fibro-adipogenic progenitors in HFD-EX (p < 0.05 vs. CON). Additionally, the canonical pro-inflammatory marker p-NF-κB was markedly reduced in the interstitium of HFD-EX (p < 0.05 vs. CON and HFD-SED). Our findings suggest that in mice with preneoplastic colorectal lesions, HFD followed by weight loss with exercise reduces muscle fibrosis and results in a higher content of muscle stem/progenitor cells. Novelty: Exercise improves muscle architecture in mice with preneoplastic colorectal lesion Exercise increases fibro/adipogenic progenitors and reduces inflammatory signaling in mice with preneoplastic colorectal lesions.

Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current (INa,L) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility. METHODS: Here, we investigated a possible role for CaMKII-dependent INa,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Nav1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice). RESULTS: A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity. CONCLUSIONS: These data demonstrate a novel role for CaMKII-dependent regulation of Nav1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

BACKGROUND: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function. METHODS: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease. RESULTS: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease. CONCLUSIONS: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

A Low Protein Diet during Gestation and Lactation Increases Hepatic Lipid Accumulation through Autophagy and Histone Deacetylase.

The present study examined the mechanism of a low protein (LP) diet on hepatic lipid metabolism during gestation and lactation. Timed-pregnant Sprague-Dawley rats were fed a control or an LP diet during gestation and lactation. LP dams had increased hepatic triglyceride accumulation and significantly higher aspartate/alanine transaminase ratio, accompanied by a decrease in circulating very low-density/low-density lipoprotein ratio. LC3B (Microtubule Associated Protein 1 Light Chain 3 Beta) expression was stimulated in LP dams along with increased histone acetylation. LP diet-induced co-localization of the LC3 binding motif-interacting proteins APOB or MTTP with LC3B, suggesting autophagic degradation. HDAC3 is found necessary to prevent lipid accumulation in response to amino acid deprivation in HepG2 cells. LC3B-mediated APOB protein degradation is related to increases in lipid accumulation. Conclusion: HDAC3 regulated LC3B-induced lipid accumulation potentially through autophagic degradation of APOB and MTTP in response to amino acid limitation caused by a low protein diet.

The Regulation of Lipokines by Environmental Factors.

Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent years, the role of lipokines, which are lipid species predominantly secreted from adipose tissue that act as hormonal regulators in many metabolic tissues, has been an important area of research for obesity and diabetes. Previous studies have identified that these secreted lipids, including palmitoleate, 12,13-diHOME, and fatty acid-hydroxy-fatty acids (FAHFA) species, are important regulators of metabolism. Moreover, environmental factors that directly affect the secretion of lipokines such as diet, exercise, and exposure to cold temperatures constitute attractive therapeutic strategies, but the mechanisms that regulate lipokine stimulation have not been thoroughly reviewed. In this study, we will discuss the chemical characteristics of lipokines that position them as attractive targets for chronic disease treatment and prevention and the emerging roles of lipokines as regulators of inter-tissue communication. We will define the target tissues of lipokines, and explore the ability of lipokines to prevent or delay the onset and development of chronic diseases. Comprehensive understanding of the lipokine synthesis and lipokine-driven regulation of metabolic outcomes is instrumental for developing novel preventative and therapeutic strategies that harness adipose tissue-derived lipokines.

Tissue-specific changes in Srebf1 and Srebf2 expression and DNA methylation with perinatal phthalate exposure.

Perinatal exposure to endocrine disrupting chemicals negatively impacts health, but the mechanism by which such toxicants damage long-term reproductive and metabolic function is unknown. Lipid metabolism plays a pivotal role in steroid hormone synthesis as well as energy utilization and storage; thus, aberrant lipid regulation may contribute to phthalate-driven health impairments. In order to test this hypothesis, we specifically examined epigenetic disruptions in lipid metabolism pathways after perinatal phthalate exposure. During gestation and lactation, pregnant Long-Evans rat dams were fed environmentally relevant doses of phthalate mixture: 0 (CON), 200 (LO), or 1000 (HI) µg/kg body weight/day. On PND90, male offspring in the LO and HI groups had higher body weights than CON rats. Gene expression of lipid metabolism pathways was altered in testis and adipose tissue of males exposed to the HI phthalate dosage. Specifically, Srebf1 was downregulated in testis and Srebf2 was upregulated in adipose tissue. In testis of HI rats, DNA methylation was increased at two loci and reduced at one other site surrounding Srebf1 transcription start site. In adipose tissue of HI rats, we observed increased DNA methylation at one region within the first intron of Srebf2. Computational analysis revealed several potential transcriptional regulator binding sites, suggesting functional relevance of the identified differentially methylated CpGs. Overall, we show that perinatal phthalate exposure affects lipid metabolism gene expression in a tissue-specific manner possibly through altering DNA methylation of Srebf1 and Srebf2.