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Circadian clocks temporally orchestrate biological processes critical for cellular/organ function. For example, the cardiomyocyte circadian clock modulates cardiac metabolism, signaling, and electrophysiology over the course of the day, such that, disruption of the clock leads to age-onset cardiomyopathy (through unknown mechanisms). Here, we report that genetic disruption of the cardiomyocyte clock results in chronic induction of the transcriptional repressor E4BP4. Importantly, E4BP4 deletion prevents age-onset cardiomyopathy following clock disruption. These studies also indicate that E4BP4 regulates both cardiac metabolism (eg, fatty acid oxidation) and electrophysiology (eg, QT interval). Collectively, these studies reveal that E4BP4 is a novel regulator of both cardiac physiology and pathophysiology.
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BACKGROUND: Leptin resistance occurs with obesity, but it is unknown if individuals at risk for obesity develop leptin resistance prior to obesity. OBJECTIVE: Investigate whether leptin resistance is independent of weight status in children at risk for obesity due to intrauterine exposure to maternal obesity or gestational diabetes mellitus (GDM). METHODS: Mother-child dyads (N = 179) were grouped by maternal pregnancy weight and GDM status: (1) normal weight, no GDM; (2) overweight/obesity, no GDM; (3) overweight/obesity with GDM. Children (4-10 years) were further stratified by current body mass index (BMI) <85th or ≥85th percentile. Leptin resistance of children and mothers was calculated as fasting leptin/fat mass index. Two-way ANOVA was used to assess whether leptin concentrations and leptin resistance differed by current weight status or in utero exposure group, after adjusting for race, sex and Tanner stage. RESULTS: Children with a BMI ≥85th percentile had more leptin resistance than those with a BMI <85th percentile (p < 0.001), but leptin resistance did not differ by in utero exposure. Similarly, leptin resistance in women was associated with weight status and not prior GDM. CONCLUSIONS: Results suggest that leptin concentrations are associated with obesity but not risk for obesity based on in utero exposure to maternal obesity or GDM.
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Diabetes Gestacional , Obesidad Materna , Femenino , Humanos , Embarazo , Peso al Nacer , Índice de Masa Corporal , Diabetes Gestacional/epidemiología , Leptina , Obesidad/epidemiología , Obesidad/complicaciones , Obesidad Materna/complicaciones , Sobrepeso/complicaciones , Factores de Riesgo , Preescolar , NiñoRESUMEN
OBJECTIVE: A buildup of skeletal muscle plasma membrane (PM) cholesterol content in mice occurs within 1 week of a Western-style high-fat diet and causes insulin resistance. The mechanism driving this cholesterol accumulation and insulin resistance is not known. Promising cell data implicate that the hexosamine biosynthesis pathway (HBP) triggers a cholesterolgenic response via increasing the transcriptional activity of Sp1. In this study we aimed to determine whether increased HBP/Sp1 activity represented a preventable cause of insulin resistance. METHODS: C57BL/6NJ mice were fed either a low-fat (LF, 10% kcal) or high-fat (HF, 45% kcal) diet for 1 week. During this 1-week diet the mice were treated daily with either saline or mithramycin-A (MTM), a specific Sp1/DNA-binding inhibitor. A series of metabolic and tissue analyses were then performed on these mice, as well as on mice with targeted skeletal muscle overexpression of the rate-limiting HBP enzyme glutamine-fructose-6-phosphate-amidotransferase (GFAT) that were maintained on a regular chow diet. RESULTS: Saline-treated mice fed this HF diet for 1 week did not have an increase in adiposity, lean mass, or body mass while displaying early insulin resistance. Consistent with an HBP/Sp1 cholesterolgenic response, Sp1 displayed increased O-GlcNAcylation and binding to the HMGCR promoter that increased HMGCR expression in skeletal muscle from saline-treated HF-fed mice. Skeletal muscle from these saline-treated HF-fed mice also showed a resultant elevation of PM cholesterol with an accompanying loss of cortical filamentous actin (F-actin) that is essential for insulin-stimulated glucose transport. Treating these mice daily with MTM during the 1-week HF diet fully prevented the diet-induced Sp1 cholesterolgenic response, loss of cortical F-actin, and development of insulin resistance. Similarly, increases in HMGCR expression and cholesterol were measured in muscle from GFAT transgenic mice compared to age- and weight-match wildtype littermate control mice. In the GFAT Tg mice we found that these increases were alleviated by MTM. CONCLUSIONS: These data identify increased HBP/Sp1 activity as an early mechanism of diet-induced insulin resistance. Therapies targeting this mechanism may decelerate T2D development.
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Resistencia a la Insulina , Ratones , Animales , Resistencia a la Insulina/fisiología , Actinas/metabolismo , Ratones Endogámicos C57BL , Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Transgénicos , Hexosaminas/metabolismoRESUMEN
As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN-designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity-focused investigators and next-step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.
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American Heart Association , Sobrepeso , Animales , Humanos , Sobrepeso/epidemiología , Sobrepeso/terapia , Obesidad/epidemiología , Obesidad/terapia , Causalidad , New YorkRESUMEN
Objective: Obesity in pregnancy and gestational diabetes (GDM) increase cardiometabolic disease risk but are difficult to disentangle. This study aimed to test the hypothesis that 4-10 years after a pregnancy complicated by overweight/obesity and GDM (OB-GDM), women and children would have greater adiposity and poorer cardiometabolic health than those with overweight/obesity (OB) or normal weight (NW) and no GDM during the index pregnancy. Methods: In this cross-sectional study, mother-child dyads were stratified into three groups based on maternal health status during pregnancy (OB-GDM = 67; OB = 76; NW = 76). Weight, height, waist and hip circumferences, and blood pressure were measured, along with fasting glucose, insulin, HbA1c, lipids, adipokines, and cytokines. Results: Women in the OB and OB-GDM groups had greater current adiposity and poorer cardiometabolic health outcomes than those in the NW group (p < 0.05). After adjusting for current adiposity, women in the OB-GDM group had higher HbA1c, glucose, HOMA-IR and triglycerides than NW and OB groups (p < 0.05). Among children, adiposity was greater in the OB-GDM versus NW group (p < 0.05), but other indices of cardiometabolic health did not differ. Conclusions: Poor cardiometabolic health in women with prior GDM is independent of current adiposity. Although greater adiposity among children exposed to GDM is evident at 4-10 years, differences in cardiometabolic health may not emerge until later.
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Long-term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We used a liver-specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin receptor (INSR) and GCGR cross talk. RictorΔLiver mice were characterized by impaired AKT signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/ßSer21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr308 was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell-autonomous cross talk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action.
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Intolerancia a la Glucosa , Hiperglucemia , Resistencia a la Insulina , Animales , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Homeostasis , Hiperglucemia/metabolismo , Insulina/metabolismo , Insulina/farmacología , Insulina Regular Humana , Hígado/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina , Receptor de Insulina/metabolismo , Receptores de Glucagón/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
While the consumption of external energy (i.e., feeding) is essential to life, this action induces a temporary disturbance of homeostasis in an animal. A primary example of this effect is found in the regulation of glycemia. In the fasted state, stored energy is released to maintain physiological glycemic levels. Liver glycogen is liberated to glucose, glycerol and (glucogenic) amino acids are used to build new glucose molecules (i.e., gluconeogenesis), and fatty acids are oxidized to fuel long-term energetic demands. This regulation is driven primarily by the counterregulatory hormones epinephrine, growth hormone, cortisol, and glucagon. Conversely, feeding induces a rapid influx of diverse nutrients, including glucose, that disrupt homeostasis. Consistently, a host of hormonal and neural systems under the coordination of insulin are engaged in the transition from fasting to prandial states to reduce this disruption. The ultimate action of these systems is to appropriately store the newly acquired energy and to return to the homeostatic norm. Thus, at first glance it is tempting to assume that glucagon is solely antagonistic regarding the anabolic effects of insulin. We have been intrigued by the role of glucagon in the prandial transition and have attempted to delineate its role as beneficial or inhibitory to glycemic control. The following review highlights this long-known yet poorly understood hormone.
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Glucagón , Insulina , Animales , Glucemia/metabolismo , Glucagón/metabolismo , Glucosa/metabolismo , Hepatocitos/metabolismo , Insulina/metabolismo , Insulina Regular Humana , Hígado/metabolismo , Receptores de Glucagón/metabolismoRESUMEN
The regulation of euglycemia is essential for human health with both chronic hypoglycemia and hyperglycemia having detrimental effects. It is well documented that the incidence of type 2 diabetes increases with age and exhibits racial disparity. Interestingly, mitochondrial DNA (mtDNA) damage also accumulates with age and its sequence varies with geographic maternal origins (maternal race). From these two observations, we hypothesized that mtDNA background may contribute to glucose metabolism and insulin sensitivity. Pronuclear transfer was used to generate mitochondrial-nuclear eXchange (MNX) mice to directly test this hypothesis, by assessing physiologic parameters of glucose metabolism in nuclear isogenic C57BL/6J mice harboring either a C57BL/6J (C57n:C57mt wild type-control) or C3H/HeN mtDNA (C57n:C3Hmt-MNX). All mice were fed normal chow diets. MNX mice were significantly leaner, had lower leptin levels, and were more insulin sensitive, with lower modified Homeostatic Model Assessment of Insulin Resistance (mHOMA-IR) values and enhanced insulin action when compared with their control counterparts. Further interrogation of muscle insulin signaling revealed higher phosphorylated Akt/total Akt ratios in MNX animals relative to control, consistent with greater insulin sensitivity. Overall, these results are consistent with the hypothesis that different mtDNA combinations on the same nuclear DNA (nDNA) background can significantly impact glucose metabolism and insulin sensitivity in healthy mice.NEW & NOTEWORTHY Different mitochondrial DNAs on the same nuclear genetic background can significantly impact body composition, glucose metabolism, and insulin sensitivity in healthy mice.
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ADN Mitocondrial/metabolismo , Glucosa/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Mitocondrias/metabolismo , Animales , ADN Mitocondrial/genética , Femenino , Masculino , Análisis de la Aleatorización Mendeliana , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BLRESUMEN
Genetic deletion of Src associated in mitosis of 68kDa (Sam68), a pleiotropic adaptor protein prevents high-fat diet-induced weight gain and insulin resistance. To clarify the role of Sam68 in energy metabolism in the adult stage, we generated an inducible Sam68 knockout mice. Knockout of Sam68 was induced at the age of 7-10 weeks, and then we examined the metabolic profiles of the mice. Sam68 knockout mice gained less body weight over time and at 34 or 36 weeks old, had smaller fat mass without changes in food intake and absorption efficiency. Deletion of Sam68 in mice elevated thermogenesis, increased energy expenditure, and attenuated core-temperature drop during acute cold exposure. Furthermore, we examined younger Sam68 knockout mice at 11 weeks old before their body weights deviate, and confirmed increased energy expenditure and thermogenic gene program. Thus, Sam68 is essential for the control of adipose thermogenesis and energy homeostasis in the adult.
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Proteínas Adaptadoras Transductoras de Señales/deficiencia , Metabolismo Energético , Termogénesis , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Masculino , Ratones , Ratones Noqueados , Proteínas de Unión al ARN/metabolismoRESUMEN
OBJECTIVE: Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. Exploiting the energy uncoupling capacity of BAT may reveal targets for obesity therapies. This exploitation requires a greater understanding of the transcriptional mechanisms underlying BAT function. One potential regulator of BAT is the transcriptional co-regulator LIM domain-binding protein 1 (LDB1), which acts as a dimerized scaffold, allowing for the assembly of transcriptional complexes. Utilizing a global LDB1 heterozygous mouse model, we recently reported that LDB1 might have novel roles in regulating BAT function. However, direct evidence for the LDB1 regulation of BAT thermogenesis and substrate utilization has not been elucidated. We hypothesize that brown adipocyte-expressed LDB1 is required for BAT function. METHODS: LDB1-deficient primary cells and brown adipocyte cell lines were assessed via qRT-PCR and western blotting for altered mRNA and protein levels to define the brown adipose-specific roles. We conducted chromatin immunoprecipitation with primary BAT tissue and immortalized cell lines. Potential transcriptional partners of LDB1 were revealed by conducting LIM factor surveys via qRT-PCR in mouse and human brown adipocytes. We developed a Ucp1-Cre-driven LDB1-deficiency mouse model, termed Ldb1ΔBAT, to test LDB1 function in vivo. Glucose tolerance and uptake were assessed at thermoneutrality via intraperitoneal glucose challenge and glucose tracer studies. Insulin tolerance was measured at thermoneutrality and after stimulation with cold or the administration of the ß3-adrenergic receptor (ß3-AR) agonist CL316,243. Additionally, we analyzed plasma insulin via ELISA and insulin signaling via western blotting. Lipid metabolism was evaluated via BAT weight, histology, lipid droplet morphometry, and the examination of lipid-associated mRNA. Finally, energy expenditure and cold tolerance were evaluated via indirect calorimetry and cold challenges. RESULTS: Reducing Ldb1 in vitro and in vivo resulted in altered BAT-selective mRNA, including Ucp1, Elovl3, and Dio2. In addition, there was reduced Ucp1 induction in vitro. Impacts on gene expression may be due, in part, to LDB1 occupying Ucp1 upstream regulatory domains. We also identified BAT-expressed LIM-domain factors Lmo2, Lmo4, and Lhx8, which may partner with LDB1 to mediate activity in brown adipocytes. Additionally, we observed LDB1 enrichment in human brown adipose. In vivo analysis revealed LDB1 is required for whole-body glucose and insulin tolerance, in part through reduced glucose uptake into BAT. In Ldb1ΔBAT tissue, we found significant alterations in insulin-signaling effectors. An assessment of brown adipocyte morphology and lipid droplet size revealed larger and more unilocular brown adipocytes in Ldb1ΔBAT mice, particularly after a cold challenge. Alterations in lipid handling were further supported by reductions in mRNA associated with fatty acid oxidation and mitochondrial respiration. Finally, LDB1 is required for energy expenditure and cold tolerance in both male and female mice. CONCLUSIONS: Our findings support LDB1 as a regulator of BAT function. Furthermore, given LDB1 enrichment in human brown adipose, this co-regulator may have conserved roles in human BAT.
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Tejido Adiposo Pardo/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas con Dominio LIM/metabolismo , Animales , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas con Dominio LIM/deficiencia , Proteínas con Dominio LIM/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , TranscriptomaRESUMEN
Hepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Gluconeogénesis/fisiología , Hígado/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Glucemia/metabolismo , Proteínas de Unión al ADN , Diabetes Mellitus Tipo 2/metabolismo , Regulación de la Expresión Génica , Glucagón/metabolismo , Gluconeogénesis/genética , Glucosa/metabolismo , Hepatocitos/metabolismo , Homeostasis , Humanos , Hiperglucemia , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión al ARN/genética , Factores de Transcripción/genética , Regulación hacia ArribaRESUMEN
Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon's biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease. © 2021 American Physiological Society. Compr Physiol 11:1759-1783, 2021.
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Glucagón , Insulina , Glucemia , Glucosa , Humanos , HígadoRESUMEN
Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon's weight loss effects. FGF21 signaling requires an obligate coreceptor (ß-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.
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Glucagón/metabolismo , Proteínas Klotho/metabolismo , Receptores de Glucagón/metabolismo , Transducción de Señal , Pérdida de Peso , Animales , Peso Corporal , Ingestión de Alimentos , Factores de Crecimiento de Fibroblastos/genética , Expresión Génica , Glucosa/metabolismo , Homeostasis , Proteínas Klotho/genética , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , PéptidosRESUMEN
OBJECTIVE: This study aimed to investigate both the long-term and short-term impacts of high-fat diets (HFD) or high-sucrose diets (HSD) on the normal diurnal pattern of cognitive function, protein expression, and the molecular clock in mice. METHODS: This study used both 6-month and 4-week feeding strategies by providing male C57BL/6J mice access to either a standard chow, HFD, or HSD. Spatial working memory and synaptic plasticity were assessed both day and night, and hippocampal tissue was measured for changes in NMDA and AMPA receptor subunits (GluN2B, GluA1), as well as molecular clock gene expression. RESULTS: HFD and HSD both disrupted normal day/night fluctuations in spatial working memory and synaptic plasticity. Mice fed HFD altered their food intake to consume more calories during the day. Both diets disrupted normal hippocampal clock gene expression, and HFD reduced GluN2B levels in hippocampal tissue. CONCLUSIONS: Taken together, these results suggest that both HFD and HSD induce a loss of day/night performance in spatial working memory and synaptic plasticity as well as trigger a cascade of changes that include disruption to the hippocampal molecular clock.
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Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Memoria a Corto Plazo/efectos de los fármacos , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Background Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction in diabetic subjects. The failing heart in nondiabetics tends to decrease reliance on fatty acid and glucose oxidation, and increases reliance on ketone body oxidation. In contrast, little is known regarding the mechanisms mediating this shift among all 3 substrates in diabetes mellitus. Therefore, we tested the hypothesis that changes in myocardial glucose utilization directly influence ketone body catabolism. Methods and Results We examined ventricular-cardiac tissue from the following murine models: (1) streptozotocin-induced type 1 diabetes mellitus; (2) high-fat-diet-induced glucose intolerance; and transgenic inducible cardiac-restricted expression of (3) glucose transporter 4 (transgenic inducible cardiac restricted expression of glucose transporter 4); or (4) dominant negative O-GlcNAcase. Elevated blood glucose (type 1 diabetes mellitus and high-fat diet mice) was associated with reduced cardiac expression of ß-hydroxybutyrate-dehydrogenase and succinyl-CoA:3-oxoacid CoA transferase. Increased myocardial ß-hydroxybutyrate levels were also observed in type 1 diabetes mellitus mice, suggesting a mismatch between ketone body availability and utilization. Increased cellular glucose delivery in transgenic inducible cardiac restricted expression of glucose transporter 4 mice attenuated cardiac expression of both Bdh1 and Oxct1 and reduced rates of myocardial BDH1 activity and ß-hydroxybutyrate oxidation. Moreover, elevated cardiac protein O-GlcNAcylation (a glucose-derived posttranslational modification) by dominant negative O-GlcNAcase suppressed ß-hydroxybutyrate dehydrogenase expression. Consistent with the mouse models, transcriptomic analysis confirmed suppression of BDH1 and OXCT1 in patients with type 2 diabetes mellitus and heart failure compared with nondiabetic patients. Conclusions Our results provide evidence that increased glucose leads to suppression of cardiac ketolytic capacity through multiple mechanisms and identifies a potential crosstalk between glucose and ketone body metabolism in the diabetic myocardium.
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Glucosa/metabolismo , Cuerpos Cetónicos/metabolismo , Miocardio/metabolismo , Animales , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Intolerancia a la Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Inmunoprecipitación , Masculino , Ratones , Miocitos Cardíacos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ARNRESUMEN
Targeting retinoid X receptor (RXR) has been proposed as one of the therapeutic strategies to treat individuals with metabolic syndrome, as RXR heterodimerizes with multiple nuclear receptors that regulate genes involved in metabolism. Despite numerous efforts, RXR ligands (rexinoids) have not been approved for clinical trials to treat metabolic syndrome due to the serious side effects such as hypertriglyceridemia and altered thyroid hormone axis. In this study, we demonstrate a novel rexinoid-like small molecule, UAB126, which has positive effects on metabolic syndrome without the known side effects of potent rexinoids. Oral administration of UAB126 ameliorated obesity, insulin resistance, hepatic steatosis, and hyperlipidemia without changes in food intake, physical activity, and thyroid hormone levels. RNA-sequencing analysis revealed that UAB126 regulates the expression of genes in the liver that are modulated by several nuclear receptors, including peroxisome proliferator-activated receptor α and/or liver X receptor in conjunction with RXR. Furthermore, UAB126 not only prevented but also reversed obesity-associated metabolic disorders. The results suggest that optimized modulation of RXR may be a promising strategy to treat metabolic disorders without side effects. Thus, the current study reveals that UAB126 could be an attractive therapy to treat individuals with obesity and its comorbidities.
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Dieta Alta en Grasa , Hígado Graso/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Obesidad/tratamiento farmacológico , Receptores X Retinoide/agonistas , Animales , Hígado Graso/sangre , Hiperlipidemias/sangre , Lípidos/sangre , Masculino , Ratones , Obesidad/sangreRESUMEN
AIMS: Emerging evidence suggests that during gestation the in utero environment programs metabolism and can increase risk of obesity in adult offspring. Our aim was to study how alterations in maternal diets during gestation might alter body weight evolution, circulating leptin levels and caloric intake in offspring, leading to changes in body composition. MATERIALS AND METHODS: We fed gestating rats either a control diet (CD), high fat diet (HFD) or an isocaloric low protein diet (LPD), and examined the repercussions in offspring fed similar diets post-weaning on birth weight, body weight evolution, body composition, insulin sensitivity, glucose tolerance and in the relationship between plasma leptin concentration and caloric intake in offspring during growth and development. KEY FINDS: Offspring from dams fed LPD maintained reduced body weight with greater % lean mass and consumed fewer calories despite having leptin levels similar to controls. On the other hand, offspring from dams fed a HFD were insulin resistant and maintained increased body weight and % fat mass, while consuming more calories than controls despite elevated leptin concentrations. Therefore the uterine environment, modulated primarily through maternal nutrition, modified the relationship between circulating leptin levels, body fat, and caloric intake in the offspring, and dams fed a HFD produced offspring with excess adiposity, insulin resistance, and leptin resistance into adulthood. SIGNIFICANCE: Our data indicates that in utero environmental factors affected by maternal diet program alterations in the set point around which leptin regulates body weight in offspring into adulthood contributing to obesity.
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Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Obesidad/etiología , Fenómenos Fisiologicos de la Nutrición Prenatal/fisiología , Tejido Adiposo/metabolismo , Adiposidad/fisiología , Animales , Animales Recién Nacidos , Peso al Nacer , Composición Corporal , Peso Corporal , Dieta Alta en Grasa , Grasas de la Dieta , Ingestión de Energía , Femenino , Resistencia a la Insulina , Lactancia , Leptina/metabolismo , Masculino , Obesidad/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas , Ratas Sprague-Dawley , DesteteRESUMEN
In 1921, a Canadian research team led by Frederick Banting and John Macleod succeeded in the isolation of insulin from pancreatic homogenate [...].
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Glucagón/metabolismo , Insulina/metabolismo , Páncreas/metabolismo , Glucagón/química , HumanosRESUMEN
Glucagon (GCG) is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that glucagon-receptor (GCGR) signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in diet-induced obese (DIO) mice; however, the mechanisms underlying this aspect of GCG biology remains unclear. Investigation of hepatic GCGR targets elucidated a potent and previously unknown induction of leptin receptor (Lepr) expression. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Eight-week-old control and liver-specific LEPR-deficient mice (LeprΔliver) were placed on a high-fat diet for 12 weeks and then treated with a selective GCGR agonist (IUB288) for 14 days. Liver triglycerides and gene expression were assessed in liver tissue homogenates. Administration of IUB288 in both lean and DIO mice increased hepatic Lepr isoforms a-e in acute (4 hours) and chronic (72 hours,16 days) (P < 0.05) settings. LeprΔliver mice displayed increased hepatic triglycerides on a chow diet alone (P < 0.05), which persisted in a DIO state (P < 0.001), with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO control and LeprΔliver mice reduced liver triglycerides regardless of genotype (P < 0.05). Together, these data suggest that GCGR activation induces hepatic Lepr expression and, although hepatic glucagon and leptin signaling have similar liver lipid targets, these appear to be 2 distinct pathways.
Asunto(s)
Hígado Graso/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Péptidos/farmacología , Receptores de Glucagón/metabolismo , Receptores de Leptina/metabolismo , Animales , Área Bajo la Curva , Dieta Alta en Grasa , Homeostasis , Metabolismo de los Lípidos/fisiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Noqueados , Obesidad/inducido químicamente , Receptores de Glucagón/genética , Receptores de Leptina/genética , Transducción de SeñalRESUMEN
Glucagon's ability to increase energy expenditure has been known for more than 60 years, yet the mechanisms underlining glucagon's thermogenic effect still remain largely elusive. Over the last years, significant efforts were directed to unravel the physiological and cellular underpinnings of how glucagon regulates energy expenditure. In this review, we summarize the current knowledge on how glucagon regulates systems metabolism with a special emphasis on its acute and chronic thermogenic effects.