RESUMEN
Secretory phospholipase A2 group IIA (PLA2G2A) is a phospholipase which has a role in inflammation, atherogenesis, and host defense. Previously, we found that PLA2G2A protects mice on high-fat diets from weight gain and insulin resistance. Here, we examined the regulation of PLA2G2A and the metabolic changes that occur in response to variations in thyroid status. In particular, the impact of PLA2G2A on the brown adipose tissue (BAT) thermogenic gene expression was explored. We induced hypothyroidism in C57BL/6 and PLA2G2A-overexpressing (IIA+) mice over a 10 wk period or treated them with thyroid hormone (T3) for 5 wk. There were no significant changes in PLA2G2A abundance in response to thyroid status. The energy expenditure of hypothyroid IIA+ mice did not increase; however, the energy expenditure, substrate utilization, insulin sensitivity, and glucose tolerance were all elevated in the IIA+ mice given T3. Moreover, white adipocytes from IIA+ mice were much more prone to "beiging," including increased expression of brown adipose thermogenic markers such as uncoupling protein 1 (UCP1), PR domain containing 16, and early B cell factor 2. Finally, the BAT of IIA+ mice had increased UCP1 and other proteins indicative of mitochondrial uncoupling and nonshivering adaptive thermogenesis. These data reveal a novel role for PLA2G2A on adipose tissue thermogenesis depending on thyroid status.-Kuefner, M. S., Deng, X., Stephenson, E. J., Pham, K., Park, E. A. Secretory phospholipase A2 group IIA enhances the metabolic rate and increases glucose utilization in response to thyroid hormone.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Hipotiroidismo/tratamiento farmacológico , Triyodotironina/farmacología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Femenino , Fosfolipasas A2 Grupo II/genética , Hipotiroidismo/metabolismo , Hipotiroidismo/patología , Insulina/metabolismo , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , TermogénesisRESUMEN
Duchenne muscular dystrophy (DMD) is a neuromuscular disease that predominantly affects boys as a result of mutation(s) in the dystrophin gene. DMD is characterized by musculoskeletal and cardiopulmonary complications, resulting in shorter life-span. Boys afflicted by DMD typically exhibit symptoms within 3-5 years of age and declining physical functions before attaining puberty. We hypothesized that rapidly deteriorating health of pre-pubertal boys with DMD could be due to diminished anabolic actions of androgens in muscle, and that intervention with an androgen receptor (AR) agonist will reverse musculoskeletal complications and extend survival. While castration of dystrophin and utrophin double mutant (mdx-dm) mice to mimic pre-pubertal nadir androgen condition resulted in premature death, maintenance of androgen levels extended the survival. Non-steroidal selective-AR modulator, GTx-026, which selectively builds muscle and bone was tested in X-linked muscular dystrophy mice (mdx). GTx-026 significantly increased body weight, lean mass and grip strength by 60-80% over vehicle-treated mdx mice. While vehicle-treated castrated mdx mice exhibited cardiopulmonary impairment and fibrosis of heart and lungs, GTx-026 returned cardiopulmonary function and intensity of fibrosis to healthy control levels. GTx-026 elicits its musculoskeletal effects through pathways that are distinct from dystrophin-regulated pathways, making AR agonists ideal candidates for combination approaches. While castration of mdx-dm mice resulted in weaker muscle and shorter survival, GTx-026 treatment increased the muscle mass, function and survival, indicating that androgens are important for extended survival. These preclinical results support the importance of androgens and the need for intervention with AR agonists to treat DMD-affected boys.
Asunto(s)
Andrógenos/metabolismo , Distrofia Muscular de Duchenne/genética , Andrógenos/genética , Animales , Modelos Animales de Enfermedad , Distrofina/genética , Fibrosis , Masculino , Ratones , Ratones Endogámicos mdx , Debilidad Muscular/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/genética , Distrofia Muscular de Duchenne/metabolismo , Receptores Androgénicos/metabolismo , Maduración Sexual , Utrofina/genéticaRESUMEN
Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1-/-, -e2-/-, -e4-/-, and -e6-/-) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1-/- and Bdnf-e2-/- mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1-/- and Bdnf-e2-/- mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4-/- and Bdnf-e6-/- mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1-/- and Bdnf-e2-/- mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1-/- and Bdnf-e2-/- mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity.
Asunto(s)
Composición Corporal/genética , Peso Corporal/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Obesidad/genética , Regiones Promotoras Genéticas , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Calorimetría Indirecta , Ingestión de Alimentos/genética , Metabolismo Energético/genética , Ratones , Ratones Transgénicos , Obesidad/metabolismo , FenotipoRESUMEN
Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases that have been implicated in inflammation, atherogenesis, and antibacterial actions. Here, we evaluated the role of PLA2G2A in the metabolic response to a high fat diet. C57BL/6 (BL/6) mice do not express PLA2g2a due to a frameshift mutation. We fed BL/6 mice expressing the human PLA2G2A gene (IIA+ mice) a fat diet and assessed the physiologic response. After 10 weeks on the high fat diet, the BL/6 mice were obese, but the IIA+ mice did not gain weight or accumulate lipid. The lean mass in chow- and high fat-fed IIA+ mice was constant and similar to the BL/6 mice on a chow diet. Surprisingly, the IIA+ mice had an elevated metabolic rate, which was not due to differences in physical activity. The IIA+ mice were more insulin sensitive and glucose tolerant than the BL/6 mice, even when the IIA+ mice were provided the high fat diet. The IIA+ mice had increased expression of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), and PPARγ coactivator 1α (PGC-1α) in brown adipose tissue (BAT), suggesting that PLA2G2A activates mitochondrial uncoupling in BAT. Our data indicate that PLA2G2A has a previously undiscovered impact on insulin sensitivity and metabolism.
Asunto(s)
Fosfolipasas A2 Grupo II/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Animales , Peso Corporal , Metabolismo Energético , Femenino , Fosfolipasas A2 Grupo II/genética , Humanos , Hígado/metabolismo , Masculino , RatonesRESUMEN
Impairments in mitochondrial function and substrate metabolism are implicated in the etiology of obesity and Type 2 diabetes. MicroRNAs (miRNAs) can degrade mRNA or repress protein translation and have been implicated in the development of such disorders. We used a contrasting rat model system of selectively bred high- (HCR) or low- (LCR) intrinsic running capacity with established differences in metabolic health to investigate the molecular mechanisms through which miRNAs regulate target proteins mediating mitochondrial function and substrate oxidation processes. Quantification of select miRNAs using the rat miFinder miRNA PCR array revealed differential expression of 15 skeletal muscles (musculus tibialis anterior) miRNAs between HCR and LCR rats (14 with higher expression in LCR; P < 0.05). Ingenuity Pathway Analysis predicted these altered miRNAs to collectively target multiple proteins implicated in mitochondrial dysfunction and energy substrate metabolism. Total protein abundance of citrate synthase (CS; miR-19 target) and voltage-dependent anion channel 1 (miR-7a target) were higher in HCR compared with LCR cohorts (~57 and ~26%, respectively; P < 0.05). A negative correlation was observed for miR-19a-3p and CS (r = 0.32, P = 0.015) protein expression. To determine whether miR-19a-3p can regulate CS in vitro, we performed luciferase reporter and transfection assays in C2C12 myotubes. MiR-19a-3p binding to the CS untranslated region did not change luciferase reporter activity; however, miR-19a-3p transfection decreased CS protein expression (â¼70%; P < 0.05). The differential miRNA expression targeting proteins implicated in mitochondrial dysfunction and energy substrate metabolism may contribute to the molecular basis, mediating the divergent metabolic health profiles of LCR and HCR rats.
Asunto(s)
Tolerancia al Ejercicio/genética , MicroARNs/metabolismo , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Carrera , Animales , Western Blotting , Línea Celular , Citrato (si)-Sintasa/metabolismo , Metabolismo Energético/genética , Técnicas In Vitro , Ratones , Fibras Musculares Esqueléticas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Canal Aniónico 1 Dependiente del Voltaje/metabolismoRESUMEN
The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is central to the pathophysiology and treatment of metabolic disease through the receptors' ability to regulate the expression of genes involved in glucose homeostasis, adipogenesis, and lipid metabolism. However, the mechanism by which PPAR is regulated remains incompletely understood. We generated a transgenic mouse strain (ZFP-TG) that overexpressed Zfp407 primarily in muscle and heart. Transcriptome analysis by RNA-Seq identified 1,300 differentially expressed genes in the muscle of ZFP-TG mice, among which PPAR target genes were significantly enriched. Among the physiologically important PPARγ target genes, Glucose transporter (Glut)-4 mRNA and protein levels were increased in heart and muscle. The increase in Glut4 and other transcriptional effects of Zfp407 overexpression together decreased body weight and lowered plasma glucose, insulin, and HOMA-IR scores relative to control littermates. When placed on high-fat diet, ZFP-TG mice remained more glucose tolerant than their wild-type counterparts. Cell-based assays demonstrated that Zfp407 synergistically increased the transcriptional activity of all PPAR subtypes, PPARα, PPARγ, and PPARδ. The increased PPAR activity was not associated with increased PPAR mRNA or protein levels, suggesting that Zfp407 posttranslationally regulates PPAR activity. Collectively, these results demonstrate that Zfp407 overexpression improved glucose homeostasis. Thus, Zfp407 represents a new drug target for treating metabolic disease.
Asunto(s)
Glucemia/metabolismo , Proteínas de Unión al ADN/genética , Transportador de Glucosa de Tipo 4/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Animales , Dieta Alta en Grasa , Perfilación de la Expresión Génica , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/genética , Homeostasis/genética , Insulina/metabolismo , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Miocardio/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR delta/genética , PPAR delta/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Procesamiento Proteico-Postraduccional/genética , ARN Mensajero/metabolismo , Factores de Transcripción/genéticaRESUMEN
We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Radicales Libres/toxicidad , Mitocondrias Musculares/metabolismo , Material Particulado/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/toxicidad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/patología , Enfermedades Mitocondriales/inducido químicamente , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Embarazo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/patologíaRESUMEN
BACKGROUND: The increased prevalence of obesity and its co-morbidities and their strong association with inactivity have produced an 'exercise-deficient phenotype' in which individuals with a particular combination of disease-susceptible genes collide with environmental influences to cross a biological 'threshold' that ultimately manifests as overt clinical conditions (i.e., risk-factors for disease states). These risk-factors have been linked to impairments in skeletal muscle mitochondrial function. SCOPE OF REVIEW: The question of whether 'inborn' mitochondrial deficiencies and/or defective mitochondrial metabolism contribute to metabolic disease, or if environmental factors are the major determinant, will be examined. MAJOR CONCLUSIONS: We contend that impaired whole-body insulin resistance along with impaired skeletal muscle handling of carbohydrate and lipid fuels (i.e., metabolic inflexibility) is associated with a reduced skeletal muscle mitochondrial content which, in large part, is a maladaptive response to an 'inactivity cycle' which predisposes to a reduced level of habitual physical activity. While genetic components play a role in the pathogenesis of metabolic disease, exercise is a powerful environmental stimulus capable of restoring the metabolic flexibility of fuel selection and reduces risk-factors for metabolic disease in genetically-susceptible individuals. GENERAL SIGNIFICANCE: Given the apathy towards voluntary physical activity in most Western societies, it is clear that there is an urgent need for innovative, clinically-effective exercise strategies, coupled with changes in current attitudes and methods of delivering exercise prescription and dietary advice, in order to improve metabolic health and reduce metabolic disease risk at the population level. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
Asunto(s)
Interacción Gen-Ambiente , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/genética , Mitocondrias/fisiología , Conducta Sedentaria , Animales , Ejercicio Físico/fisiología , Humanos , Aptitud FísicaRESUMEN
Impaired visceral white adipose tissue (WAT) metabolism has been implicated in the pathogenesis of several lifestyle-related disease states, with diminished expression of several WAT mitochondrial genes reported in both insulin-resistant humans and rodents. We have used rat models selectively bred for low- (LCR) or high-intrinsic running capacity (HCR) that present simultaneously with divergent metabolic phenotypes to test the hypothesis that oxidative enzyme expression is reduced in epididymal WAT from LCR animals. Based on this assumption, we further hypothesized that short-term exercise training (6 wk of treadmill running) would ameliorate this deficit. Approximately 22-wk-old rats (generation 22) were studied. In untrained rats, the abundance of mitochondrial respiratory complexes I-V, citrate synthase (CS), and PGC-1 was similar for both phenotypes, although CS activity was greater than 50% in HCR (P = 0.09). Exercise training increased CS activity in both phenotypes but did not alter mitochondrial protein content. Training increased the expression and phosphorylation of proteins with roles in ß-adrenergic signaling, including ß3-adrenergic receptor (16% increase in LCR; P < 0.05), NOR1 (24% decrease in LCR, 21% decrease in HCR; P < 0.05), phospho-ATGL (25% increase in HCR; P < 0.05), perilipin (25% increase in HCR; P < 0.05), CGI-58 (15% increase in LCR; P < 0.05), and GLUT4 (16% increase in HCR; P < 0.0001). A training effect was also observed for phospho-p38 MAPK (12% decrease in LCR, 20% decrease in HCR; P < 0.05) and phospho-JNK (29% increase in LCR, 20% increase in HCR; P < 0.05). We conclude that in the LCR-HCR model system, mitochondrial protein expression in WAT is not affected by intrinsic running capacity or exercise training. However, training does induce alterations in the activity and expression of several proteins that are essential to the intracellular regulation of WAT metabolism.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Condicionamiento Físico Animal/fisiología , Resistencia Física/genética , Resistencia Física/fisiología , Carrera/fisiología , Animales , Western Blotting , Peso Corporal/fisiología , Citrato (si)-Sintasa/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Transportador de Glucosa de Tipo 4/biosíntesis , Transportador de Glucosa de Tipo 4/genética , Lipólisis/fisiología , Masculino , Proteínas Mitocondriales/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/biosíntesis , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas Quinasas/metabolismo , Proteínas de Unión al ARN/biosíntesis , Proteínas de Unión al ARN/genética , Ratas , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
Rats selectively bred for low (LCR) or high (HCR) intrinsic running capacity simultaneously present with contrasting risk factors for cardiovascular and metabolic disease. However, the impact of these phenotypes on left ventricular (LV) morphology and microvascular function, and their progression with aging, remains unresolved. We tested the hypothesis that the LCR phenotype induces progressive age-dependent LV remodeling and impairments in microvascular function, glucose utilization, and ß-adrenergic responsiveness, compared with HCR. Hearts and vessels isolated from female LCR (n = 22) or HCR (n = 26) were studied at 12 and 35 wk. Nonselected N:NIH founder rats (11 wk) were also investigated (n = 12). LCR had impaired glucose tolerance and elevated plasma insulin (but not glucose) and body-mass at 12 wk compared with HCR, with early LV remodeling. By 35 wk, LV prohypertrophic and glucose transporter GLUT4 gene expression were up- and downregulated, respectively. No differences in LV ß-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function was predominantly nitric oxide (NO)-mediated in both phenotypes and remained intact in LCR for both age-groups. In contrast, mesenteric arteries microvascular endothelial function, which was impaired in LCR rats regardless of age. At 35 wk, endothelial-derived hyperpolarizing factor-mediated relaxation was impaired whereas the NO contribution to relaxation is intact. Furthermore, there was reduced ß2-adrenoceptor responsiveness in both aorta and mesenteric LCR arteries. In conclusion, diminished intrinsic exercise capacity impairs systemic glucose tolerance and is accompanied by progressive development of LV remodeling. Impaired microvascular perfusion is a likely contributing factor to the cardiac phenotype.
Asunto(s)
Envejecimiento/fisiología , Circulación Coronaria/fisiología , Tolerancia al Ejercicio/fisiología , Corazón/fisiología , Remodelación Ventricular/fisiología , Envejecimiento/genética , Animales , Factores Biológicos/metabolismo , Tolerancia al Ejercicio/genética , Femenino , Fibrosis/fisiopatología , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Síndrome Metabólico/genética , Síndrome Metabólico/fisiopatología , Microcirculación/fisiología , Miocitos Cardíacos/fisiología , Óxido Nítrico/metabolismo , Fenotipo , Ratas , Ratas Endogámicas , Receptores Adrenérgicos beta/metabolismo , Transducción de Señal/fisiología , Resistencia Vascular/fisiología , Vasodilatación/fisiología , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismoRESUMEN
OBJECTIVE: Alström syndrome (AS) is a rare multisystem disorder of which early onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on ALMS1. METHODS: Comprehensive energy balance phenotyping was performed on Alms1tvrm102 mice at both 8 and 18 weeks of age. RESULTS: It was found that adiposity gains occurred early and rapidly in Alms1tvrm102 male mice but much later in females. Rapid increases in body fat in males were due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1tvrm102 mice did not persist as mice aged. CONCLUSIONS: Either loss of ALMS1 causes a developmental delay in the mechanisms controlling early life EE or activation of compensatory mechanisms occurs after obesity is established in AS. Future studies will determine how ALMS1 modulates EE and how sex moderates this process.
Asunto(s)
Síndrome de Alstrom , Obesidad Infantil , Femenino , Masculino , Niño , Humanos , Ratones , Animales , Anciano , Síndrome de Alstrom/genética , Proteínas de Ciclo Celular/genética , Modelos Animales de Enfermedad , Tejido AdiposoRESUMEN
Obesity is associated with chronic multi-system bioenergetic stress that may be improved by increasing the number of healthy mitochondria available across organ systems. However, treatments capable of increasing mitochondrial content are generally limited to endurance exercise training paradigms, which are not always sustainable long-term, let alone feasible for many patients with obesity. Recent studies have shown that local transfer of exogenous mitochondria from healthy donor tissues can improve bioenergetic outcomes and alleviate the effects of tissue injury in recipients with organ specific disease. Thus, the aim of this project was to determine the feasibility of systemic mitochondrial transfer for improving energy balance regulation in the setting of diet-induced obesity. We found that transplantation of mitochondria from lean mice into mice with diet-induced obesity attenuated adiposity gains by increasing energy expenditure and promoting the mobilization and oxidation of lipids. Additionally, mice that received exogenous mitochondria demonstrated improved glucose uptake, greater insulin responsiveness, and complete reversal of hepatic steatosis. These changes were, in part, driven by adaptations occurring in white adipose tissue. Together, these findings are proof-of-principle that mitochondrial transplantation is an effective therapeutic strategy for limiting the deleterious metabolic effects of diet-induced obesity in mice.
RESUMEN
Obesity-induced lipid oversupply promotes skeletal muscle mitochondrial biogenesis. Previous investigations have utilized extreme high-fat diets (HFD) to induce such mitochondrial perturbations despite their disparity from human obesogenic diets. Here, we evaluate the effects of Western diet (WD)-induced obesity on skeletal muscle mitochondrial function. Long-Evans rats were given ad libitum access to either a WD [40% energy (E) from fat, 17% protein, and 43% carbohydrate (30% sucrose); n = 12] or a control diet (CON; 16% of E from fat, 21% protein, and 63% carbohydrate; n = 12) for 12 wk. Rats fed the WD consumed 23% more E than CON (P = 0.0001), which was associated with greater increases in body mass (23%, P = 0.0002) and adiposity (17%, P = 0.03). There were no differences in fasting blood glucose concentration or glucose tolerance between diets, although fasting insulin was increased by 40% (P = 0.007). Fasting serum triglycerides were also elevated in WD (86%, P = 0.001). The maximal capacity of the electron transfer system was greater following WD (37%, P = 0.02), as were the maximal activities of several mitochondrial enzymes (citrate synthase, ß-hydroxyacyl-CoA dehydrogenase, carnitine palmitoyltransferase). Protein expression of citrate synthase, UCP3, and individual respiratory complexes was greater after WD (P < 0.05) despite no differences in the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARδ, or PPARγ coactivator-1 mRNA or protein abundance. We conclude that the respiratory capacity of skeletal muscle is enhanced in response to the excess energy supplied by a WD. This is likely due to an increase in mitochondrial density, which at least in the short term, and in the absence of increased energy demand, may protect the tissue from lipid-induced impairments in glycemic control.
Asunto(s)
Dieta/efectos adversos , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Consumo de Oxígeno/fisiología , Animales , Western Blotting , Peso Corporal/fisiología , Carbohidratos de la Dieta/farmacología , Grasas de la Dieta/farmacología , Ingestión de Energía/fisiología , Ayuno/fisiología , Prueba de Tolerancia a la Glucosa , Hiperinsulinismo/metabolismo , Masculino , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/metabolismo , Músculo Esquelético/enzimología , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Long-Evans , Reacción en Cadena en Tiempo Real de la Polimerasa , Sacarosa/farmacología , Factores de Transcripción/metabolismo , Triglicéridos/metabolismoRESUMEN
Researchers are exploring sex differences in experimental models of both development and disease-but are we doing enough? In this collection of Voices, we celebrate researchers who are asking this question and starting to offer mechanistic clues on sexually dimorphic differences seen in interorgan communication, metabolic disease, neurological disorders, and more.
Asunto(s)
Caracteres Sexuales , Voz , Masculino , Humanos , FemeninoRESUMEN
Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Tejido Adiposo/metabolismo , Animales , Sacarosa en la Dieta/efectos adversos , Ácidos Grasos/metabolismo , Humanos , Insulina/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismoRESUMEN
Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for type 2 diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than nonrisk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet-fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased use of carbohydrates as an energy source. Fasting- and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice, and concomitantly, adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and nonesterified fatty acid less efficiently than wild-type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.
Asunto(s)
Adiposidad , Diabetes Mellitus Tipo 2 , Factores de Transcripción de Tipo Kruppel , Metabolismo de los Lípidos , Factores Sexuales , Adipocitos/metabolismo , Adiposidad/genética , Animales , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Metabolismo de los Lípidos/genética , Masculino , Ratones , Obesidad/genética , Obesidad/metabolismoRESUMEN
We have used a novel model of genetically imparted endurance exercise capacity and metabolic health to study the genetic and environmental contributions to skeletal muscle glucose and lipid metabolism. We hypothesized that metabolic abnormalities associated with low intrinsic running capacity would be ameliorated by exercise training. Selective breeding for 22 generations resulted in rat models with a fivefold difference in intrinsic aerobic capacity. Low (LCR)- and high (HCR)-capacity runners remained sedentary (SED) or underwent 6 wk of exercise training (EXT). Insulin-stimulated glucose transport, insulin signal transduction, and rates of palmitate oxidation were lower in LCR SED vs. HCR SED (P < 0.05). Decreases in glucose and lipid metabolism were associated with decreased ß2-adrenergic receptor (ß2-AR), and reduced expression of Nur77 target proteins that are critical regulators of muscle glucose and lipid metabolism [uncoupling protein-3 (UCP3), fatty acid transporter (FAT)/CD36; P < 0.01 and P < 0.05, respectively]. EXT reversed the impairments to glucose and lipid metabolism observed in the skeletal muscle of LCR, while increasing the expression of ß2-AR, Nur77, GLUT4, UCP3, and FAT/CD36 (P < 0.05) in this tissue. However, no metabolic improvements were observed following exercise training in HCR. Our results demonstrate that metabolic impairments resulting from genetic factors (low intrinsic aerobic capacity) can be overcome by an environmental intervention (exercise training). Furthermore, we identify Nur77 as a potential mechanism for improved skeletal muscle metabolism in response to EXT.
Asunto(s)
Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Resistencia Física/genética , Resistencia Física/fisiología , Animales , Metabolismo de los Hidratos de Carbono/genética , Metabolismo de los Hidratos de Carbono/fisiología , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/fisiología , Modelos Animales , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/fisiología , Ratas , Ratas Endogámicas , Receptores Adrenérgicos beta/fisiología , Transducción de Señal/fisiologíaRESUMEN
The purpose of this study was to determine the effects of glucocorticoid-induced metabolic dysfunction in the presence of diet-induced obesity. C57BL/6J adult male lean and diet-induced obese mice were given dexamethasone, and levels of hepatic steatosis, insulin resistance, and lipolysis were determined. Obese mice given dexamethasone had significant, synergistic effects on fasting glucose, insulin resistance, and markers of lipolysis, as well as hepatic steatosis. This was associated with synergistic transactivation of the lipolytic enzyme adipose triglyceride lipase. The combination of chronically elevated glucocorticoids and obesity leads to exacerbations in metabolic dysfunction. Our findings suggest lipolysis may be a key player in glucocorticoid-induced insulin resistance and fatty liver in individuals with obesity.
Asunto(s)
Dexametasona/farmacología , Glucocorticoides/farmacología , Resistencia a la Insulina , Obesidad/metabolismo , Obesidad/patología , Células 3T3-L1 , Animales , Progresión de la Enfermedad , Metabolismo Energético/efectos de los fármacos , Resistencia a la Insulina/fisiología , Lipólisis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones ObesosRESUMEN
Glucocorticoids have major effects on adipose tissue metabolism. To study tissue mRNA expression changes induced by chronic elevated endogenous glucocorticoids, we performed RNA sequencing on the subcutaneous adipose tissue from patients with Cushing's disease (n=5) compared to patients with nonfunctioning pituitary adenomas (n=11). We found a higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as a decreased expression of transcripts involved in inflammation and protein synthesis. To further study this in a model system, we subjected mice to dexamethasone treatment for 12 weeks and analyzed their inguinal (subcutaneous) fat pads, which led to similar findings. Additionally, mice treated with dexamethasone showed drastic decreases in lean body mass as well as increased fat mass, further supporting the human transcriptomic data. These data provide insight to transcriptional changes that may be responsible for the comorbidities associated with chronic elevations of glucocorticoids.
Asunto(s)
Síndrome de Cushing/genética , Obesidad/genética , ARN Mensajero/genética , Grasa Subcutánea/citología , Grasa Subcutánea/metabolismo , Animales , Secuencia de Bases , Ceramidas/análisis , Síndrome de Cushing/fisiopatología , Dexametasona/farmacología , Modelos Animales de Enfermedad , Glucosa/metabolismo , Humanos , Inflamación/genética , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Lipogénesis/genética , Lipólisis/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Oxidación-Reducción , Neoplasias Hipofisarias/genética , Biosíntesis de Proteínas/genética , Proteolisis , Análisis de Secuencia de ARN , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
Type 2 diabetes mellitus and its precursor, insulin resistance, are metabolic disease states characterized by impaired regulation in the delivery, transport, and/or storage of energy substrates (primarily carbohydrate- and fat-based fuels). A hallmark feature of patients with type 2 diabetes is prolonged periods of hyperglycemia due to a decreased responsiveness of metabolically active peripheral tissues to the actions of insulin (i.e., metabolic inflexibility). Accordingly, efforts to modify skeletal muscle substrate handling in type 2 diabetes patients so that the capacity for fat oxidation and metabolic flexibility is improved should be a primary goal for the treatment of these disorders. Two potent interventions for improving whole-body glucose homeostasis are exercise and diet. A single bout of either resistance or endurance exercise reduces the prevalence and duration of hyperglycemic excursions in patients with type 2 diabetes, an effect lasting well into the next day. With regard to diet, the carbohydrate content of a meal and the glycemic index (GI) of the carbohydrate consumed are both major determinants of the postprandial glycemic response. Diets containing high-GI carbohydrates have been shown to be independent risk factors for type 2 diabetes onset, while in obese insulin-resistant individuals, low-GI diets are effective for inducing both weight loss and improving insulin action and glucose tolerance. The implementation of physical activity and dietary modifications are effective low-cost treatment options for controlling hyperglycemic episodes in patients with type 2 diabetes.