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17ß-Estradiol is an ovarian hormone that regulates energy circulation and storage by acting on the central nervous system. However, the metabolic differences between the blood and brain when stimulated by 17ß-estradiol are poorly understood. Moreover, research using menopause-induced models to investigate primary metabolites in the blood and brain is limited. Thus, this study aimed to identify metabolic changes in the plasma and brain resulting from 17ß-estradiol supplementation in an estrogen-deficient mouse model. Three groups of mice were utilized: sham-operated mice (Sham), ovariectomized mice (OVX), and ovariectomized mice that received a weekly supplementation of 17ß-estradiol (E2). Plasma and brain samples from these mice were subjected to metabolic analysis using gas chromatography-time-of-flight-mass spectrometry. Compared with the plasma samples from the Sham and OVX groups, the plasma samples from the E2 group contained higher contents of branched-chain amino acids (BCAAs), such as valine, isoleucine, and leucine. Meanwhile, the brain samples from the E2 group contained higher contents of most metabolites, including BCAAs, neurotransmitters, tricarboxylic acid cycle intermediates, and fatty acids, than those from the two other groups. This study is the first to reveal differences in energy metabolism induced by 17ß-estradiol supplementation through brain metabolic profiling of ovariectomized mice, emphasizing the importance of brain metabolic profiling in menopausal hormone research.
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Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Glucosa , SodioRESUMEN
BACKGRUOUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors. METHODS: Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice. RESULTS: Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus. CONCLUSION: This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.
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Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Ratones , Animales , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Hipotálamo/metabolismo , Glucosa/metabolismo , Fenotipo , Neuronas/metabolismo , Sodio/metabolismoRESUMEN
Cisplatin is a chemotherapeutic drug commonly used for treating different types of cancer. However, long-term use can lead to side effects, including anorexia, nausea, vomiting, and weight loss, which negatively affect the patient's quality of life and ability to undergo chemotherapy. This study aimed to investigate the mechanisms underlying the development of a negative energy balance during cisplatin treatment. Mice treated with cisplatin exhibit reduced food intake, body weight, and energy expenditure. We observed altered neuronal activity in the hypothalamic nuclei involved in the regulation of energy metabolism in cisplatin-treated mice. In addition, we observed activation of microglia and inflammation in the hypothalamus following treatment with cisplatin. Consistent with this finding, inhibition of microglial activation effectively rescued cisplatin-induced anorexia and body weight loss. The present study identified the role of hypothalamic neurons and inflammation linked to microglial activation in the anorexia and body weight loss observed during cisplatin treatment. These findings provide insight into the mechanisms underlying the development of metabolic abnormalities during cisplatin treatment and suggest new strategies for managing these side effects.
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TTF-1 stimulates appetite by regulating the expression of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) genes in the hypothalamus of starving animals. However, the mechanism underlying TTF-1's response to decreased energy levels remains elusive. Here, we provide evidence that the NAD+-dependent deacetylase, sirtuin1 (Sirt1), activates TTF-1 in response to energy deficiency. Energy deficiency leads to a twofold increase in the expression of both Sirt1 and TTF-1, leading to the deacetylation of TTF-1 through the interaction between the two proteins. The activation of Sirt1, induced by energy deficiency or resveratrol treatment, leads to a significant increase in the deacetylation of TTF-1 and promotes its nuclear translocation. Conversely, the inhibition of Sirt1 prevents these Sirt1 effects. Notably, a point mutation in a lysine residue of TTF-1 significantly disrupts its deacetylation and thus nearly completely hinders its ability to regulate AgRP and POMC gene expression. These findings highlight the importance of energy-deficiency-induced deacetylation of TTF-1 in the control of AgRP and POMC gene expression.
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Proopiomelanocortina , Sirtuina 1 , Animales , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Hipotálamo/metabolismoRESUMEN
Eukaryotic translation initiation factor 2α (eIF2α) is a key mediator of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). In mammals, eIF2α is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2α (p-eIF2α) in agouti-related peptide (AgRP) neurons using a mouse model (AgRPeIF2αA/A) with an AgRP neuron-specific substitution from Ser 51 to Ala in eIF2α, which impairs eIF2α phosphorylation in AgRP neurons. These AgRPeIF2αA/A mice had decreases in starvation-induced AgRP neuronal activity and food intake and an increased responsiveness to leptin. Intriguingly, impairment of eIF2α phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2α phosphorylation regulates AgRP neuronal activity by affecting intracellular responses such as the UPR and autophagy during starvation, thereby participating in the homeostatic control of whole-body energy metabolism. ARTICLE HIGHLIGHTS: This study examines the impact of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, triggered by an energy deficit, on hypothalamic AgRP neurons and its subsequent influence on whole-body energy homeostasis. Impaired eIF2α phosphorylation diminishes the unfolded protein response and autophagy, both of which are crucial for energy deficit-induced activation of AgRP neurons. This study highlights the significance of eIF2α phosphorylation as a cellular marker indicating the availability of energy in AgRP neurons and as a molecular switch that regulates homeostatic feeding behavior.
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Factor 2 Eucariótico de Iniciación , eIF-2 Quinasa , Animales , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , eIF-2 Quinasa/metabolismo , Estrés del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Conducta Alimentaria , Mamíferos/metabolismo , Neuronas/metabolismo , Péptidos/metabolismo , Fosforilación , RatonesRESUMEN
Molecular profiling of the hypothalamus in response to metabolic shifts is a critical cue to better understand the principle of the central control of whole-body energy metabolism. The transcriptional responses of the rodent hypothalamus to short-term calorie restriction have been documented. However, studies on the identification of hypothalamic secretory factors that potentially contribute to the control of appetite are lacking. In this study, we analyzed the differential expression of hypothalamic genes and compared the selected secretory factors from the fasted mice with those of fed control mice using bulk RNA-sequencing. We verified seven secretory genes that were significantly altered in the hypothalamus of fasted mice. In addition, we determined the response of secretory genes in cultured hypothalamic cells to treatment with ghrelin and leptin. The current study provides further insights into the neuronal response to food restriction at the molecular level and may be useful for understanding the hypothalamic control of appetite.
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Hipotálamo , Inanición , Ratones , Animales , Hipotálamo/metabolismo , Leptina/metabolismo , Inanición/metabolismo , Apetito/fisiología , Ayuno/fisiología , Ghrelina/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Nutrient availability and utilization in hypothalamic cells are directly associated with the regulation of whole-body energy homeostasis. Thus, establishing metabolic profiling in the hypothalamus in response to metabolic shift is valuable to better understand the underlying mechanism of appetite regulation. In the present study, we evaluate the alteration of lipophilic and hydrophilic metabolites in both the hypothalamus and serum of fasted mice. Fasted mice displayed an elevated ketone body and decreased lactate levels in the hypothalamus. In support of the metabolite data, we further confirmed that short-term food deprivation resulted in the altered expression of genes involved in cellular metabolic processes, including the shuttling of fuel sources and the production of monocarboxylates in hypothalamic astrocytes. Overall, the current study provides useful information to close the gap in our understanding of the molecular and cellular mechanisms underlying hypothalamic control of whole-body energy metabolism.
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Tristetraprolin (TTP), an RNA-binding protein, controls the stability of RNA by capturing AU-rich elements on their target genes. It has recently been identified that TTP serves as an anti-inflammatory protein by guiding the unstable mRNAs of pro-inflammatory proteins in multiple cells. However, it has not yet been investigated whether TTP affects the inflammatory responses in the hypothalamus. Since hypothalamic inflammation is tightly coupled to the disturbance of energy homeostasis, we designed the current study to investigate whether TTP regulates hypothalamic inflammation and thereby affects energy metabolism by utilizing TTP-deficient mice. We observed that deficiency of TTP led to enhanced hypothalamic inflammation via stimulation of a variety of pro-inflammatory genes. In addition, microglial activation occurred in the hypothalamus, which was accompanied by an enhanced inflammatory response. In line with these molecular and cellular observations, we finally confirmed that deficiency of TTP results in elevated core body temperature and energy expenditure. Taken together, our findings unmask novel roles of hypothalamic TTP on energy metabolism, which is linked to inflammatory responses in hypothalamic microglial cells.
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Hipertermia/genética , Hipotálamo/patología , Microglía/metabolismo , Tristetraprolina/deficiencia , Elementos Ricos en Adenilato y Uridilato , Animales , Temperatura Corporal , Peso Corporal , Citocinas/metabolismo , Homeostasis , Inflamación , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Estabilidad del ARN , ARN Mensajero/metabolismo , Tristetraprolina/genética , Tristetraprolina/metabolismoRESUMEN
Adiponectin, an adipose tissue-derived hormone, plays integral roles in lipid and glucose metabolism in peripheral tissues, such as the skeletal muscle, adipose tissue, and liver. Moreover, it has also been shown to have an impact on metabolic processes in the central nervous system. Astrocytes comprise the most abundant cell type in the central nervous system and actively participate in metabolic processes between blood vessels and neurons. However, the ability of adiponectin to control nutrient metabolism in astrocytes has not yet been fully elucidated. In this study, we investigated the effects of adiponectin on multiple metabolic processes in hypothalamic astrocytes. Adiponectin enhanced glucose uptake, glycolytic processes and fatty acid oxidation in cultured primary hypothalamic astrocytes. In line with these findings, we also found that adiponectin treatment effectively enhanced synthesis and release of monocarboxylates. Overall, these data suggested that adiponectin triggers catabolic processes in astrocytes, thereby enhancing nutrient availability in the hypothalamus.
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Adiponectina/metabolismo , Astrocitos/metabolismo , Glucosa/metabolismo , Hipotálamo/metabolismo , Nutrientes/metabolismo , Adiponectina/genética , Animales , Astrocitos/citología , Metabolismo Energético , Femenino , Glucólisis , Hipotálamo/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-ReducciónRESUMEN
Occurrence of obesity during the postmenopausal period is closely associated with inflammatory processes in multiple peripheral organs that are metabolically active. Hypothalamic inflammation has been recognized as one of the major underlying causes of various metabolic disorders, including obesity. The association between menopause-related obesity and hypothalamic inflammation remains poorly understood. We observed an elevation in hypothalamic inflammation in the ovariectomized mice, which displayed altered metabolic phenotypes and visceral obesity. Furthermore, we confirmed that ovariectomized mice displayed microglial activation accompanied by the upregulation of multiple genes involved in the inflammatory responses in hypothalamic microglia. Collectively, the current findings suggest that hypothalamic inflammation associated with microglial functioning could be a major pathogenic element in disruption of energy homeostasis during the postmenopausal period.