RESUMO
Type 1 diabetes mellitus (T1DM) is characterized by insulin deficiency leading to hyperglycemia and several metabolic defects. Insulin therapy remains the cornerstone of T1DM management, yet it increases the risk of life-threatening hypoglycemia and the development of major comorbidities. Here, we report an insulin signaling-independent pathway able to improve glycemic control in T1DM rodents. Co-treatment with recombinant S100 calcium-binding protein A9 (S100A9) enabled increased adherence to glycemic targets with half as much insulin and without causing hypoglycemia. Mechanistically, we demonstrate that the hyperglycemia-suppressing action of S100A9 is due to a Toll-like receptor 4-dependent increase in glucose uptake in specific skeletal muscles (i.e., soleus and diaphragm). In addition, we found that T1DM mice have abnormal systemic inflammation, which is resolved by S100A9 therapy alone (or in combination with low insulin), hence uncovering a potent anti-inflammatory action of S100A9 in T1DM. In summary, our findings reveal the S100A9-TLR4 skeletal muscle axis as a promising therapeutic target for improving T1DM treatment.
Assuntos
Diabetes Mellitus Tipo 1 , Hiperglicemia , Hipoglicemia , Animais , Camundongos , Insulina/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemia/complicações , Hipoglicemia/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Calgranulina BRESUMO
Hypothalamic mTORC1 signaling is involved in nutrient sensing. Neurons that express the agouti-related protein (AgRP) are activated by food restriction and integrate interoceptive and exteroceptive signals to control food intake, energy expenditure, and other metabolic responses. To determine whether mTORC1 signaling in AgRP neurons is necessary for regulating energy and glucose homeostasis, especially in situations of negative energy balance, mice carrying ablation of the Raptor gene exclusively in AgRP-expressing cells were generated. AgRPΔRaptor mice showed no differences in body weight, fat mass, food intake, or energy expenditure; however, a slight improvement in glucose homeostasis was observed compared to the control group. When subjected to 5 days of food restriction (40% basal intake), AgRPΔRaptor female mice lost less lean body mass and showed a blunted reduction in energy expenditure, whereas AgRPΔRaptor male mice maintained a higher energy expenditure compared to control mice during the food restriction and 5 days of refeeding period. AgRPΔRaptor female mice did not exhibit the food restriction-induced increase in serum corticosterone levels. Finally, although hypothalamic fasting- or refeeding-induced Fos expression showed no differences between the groups, AgRPΔRaptor mice displayed increased hyperphagia during refeeding. Thus, some metabolic and neuroendocrine responses to food restriction are disturbed in AgRPΔRaptor mice.
Assuntos
Ingestão de Alimentos , Alvo Mecanístico do Complexo 1 de Rapamicina , Neurônios , Animais , Feminino , Masculino , Camundongos , Proteína Relacionada com Agouti/metabolismo , Ingestão de Alimentos/fisiologia , Glucose/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neurônios/metabolismoRESUMO
Many cytokines have been proposed to regulate reproduction due to their actions on hypothalamic kisspeptin cells, the main modulators of gonadotropin-releasing hormone (GnRH) neurons. Hormones such as leptin, prolactin and growth hormone are good examples of cytokines that lead to Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation, consequently exerting effects in kisspeptin neurons. Different studies have investigated how specific components of the JAK/STAT signaling pathway affect the functions of kisspeptin cells, but the role of the suppressor of cytokine signaling 3 (SOCS3) in mediating cytokine actions in kisspeptin cells remains unknown. Cre-Loxp technology was used in the present study to ablate Socs3 expression in kisspeptin cells (Kiss1/Socs3-KO). Then, male and female control and Kiss1/Socs3-KO mice were evaluated for sexual maturation, energy homeostasis features, and fertility. It was found that hypothalamic Kiss1 mRNA expression is significantly downregulated in Kiss1/Socs3-KO mice. Despite reduced hypothalamic Kiss1 mRNA content, these mice did not present any sexual maturation or fertility impairments. Additionally, body weight gain, leptin sensitivity and glucose homeostasis were similar to control mice. Interestingly, Kiss1/Socs3-KO mice were partially protected against lipopolysaccharide (LPS)-induced body weight loss. Our results suggest that Socs3 ablation in kisspeptin cells partially prevents the sickness behavior induced by LPS, suggesting that kisspeptin cells can modulate energy metabolism in mice in certain situations.
Assuntos
Kisspeptinas , Lipopolissacarídeos , Animais , Peso Corporal/fisiologia , Citocinas/metabolismo , Feminino , Kisspeptinas/genética , Kisspeptinas/metabolismo , Leptina/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , RNA Mensageiro , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Redução de PesoRESUMO
Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.
Assuntos
Diabetes Mellitus Experimental , Cetose , Animais , Calgranulina B/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Corpos Cetônicos/metabolismo , Fígado/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
Growth hormone (GH) receptor (GHR) signaling induces the phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the cells of several tissues including in the hypothalamus. During pregnancy, several STAT5-recruiting hormones (e.g., prolactin, GH and placental lactogens) are highly secreted. However, the precise contribution of GHR signaling to the surge of pSTAT5 immunoreactive neurons that occurs in the hypothalamus of pregnant mice is currently unknown. Thus, the objective of the present study was to determine whether GHR expression in neurons is required for inducing pSTAT5 expression in several hypothalamic nuclei during pregnancy. Initially, we demonstrated that late pregnant C57BL/6 mice (gestational day 14 to 18) exhibited increased pulsatile GH secretion compared to virgin females. Next, we confirmed that neuron-specific GHR ablation robustly reduces hypothalamic Ghr mRNA levels and prevents GH-induced pSTAT5 in the arcuate, paraventricular and ventromedial hypothalamic nuclei. Subsequently, the number of pSTAT5 immunoreactive cells was determined in the hypothalamus of late pregnant mice. Although neuron-specific GHR ablation did not affect the number of pSTAT5 immunoreactive cells in the paraventricular nucleus of the hypothalamus, reduced pSTAT5 expression was observed in the arcuate and ventromedial nuclei of pregnant neuron-specific GHR knockouts, compared to control pregnant mice. In summary, a subset of hypothalamic neurons requires GHR signaling to express pSTAT5 during pregnancy. These findings contribute to the understanding of the endocrine factors that affect the activation of transcription factors in the brain during pregnancy.
Assuntos
Proteínas de Transporte/metabolismo , Hipotálamo/metabolismo , Prenhez/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Proteínas de Transporte/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Placenta/metabolismo , GravidezRESUMO
Previous studies indicate that leptin receptor (LepR) expression in GABAergic neurons is necessary for the biological effects of leptin. However, it is not clear whether LepR expression only in GABAergic neurons is sufficient to prevent the metabolic and neuroendocrine imbalances caused by LepR deficiency. In the present study, we produced mice that express the LepR exclusively in GABAergic cells (LepRVGAT mice) and compared them with wild-type (LepR+/+) and LepR-deficient (LepRNull/Null) mice. Although LepRVGAT mice showed a pronounced reduction in body weight and fat mass, as compared with LepRNull/Null mice, male and female LepRVGAT mice exhibited an obese phenotype relative to LepR+/+ mice. Food intake was normalized in LepRVGAT mice; however, LepRVGAT mice still exhibited lower energy expenditure in both sexes and reduced ambulatory activity in the females, compared with LepR+/+ mice. The acute anorexigenic effect of leptin and hedonic feeding were normalized in LepRVGAT mice despite the hyperleptinemia they present. Although LepRVGAT mice showed improved glucose homeostasis compared with LepRNull/Null mice, both male and female LepRVGAT mice exhibited insulin resistance. In contrast, LepR expression only in GABAergic cells was sufficient to normalize the density of agouti-related peptide (AgRP) and α-MSH immunoreactive fibers in the paraventricular nucleus of the hypothalamus. However, LepRVGAT mice exhibited reproductive dysfunctions, including subfertility in males and alterations in the estrous cycle of females. Taken together, our findings indicate that LepR expression in GABAergic cells, although critical to the physiology of leptin, is insufficient to normalize several metabolic aspects and the reproductive function in mice.
Assuntos
Metabolismo Energético/genética , Neurônios GABAérgicos/metabolismo , Receptores para Leptina/genética , Reprodução/genética , Animais , Feminino , Ácido Glutâmico/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Receptores para Leptina/metabolismoRESUMO
Leptin is a hormone required for the regulation of body weight in adult animals. However, during the postnatal period, leptin is mostly involved in developmental processes. Because the precise moment at which leptin starts to exert its metabolic effects is not well characterized, our objective was to identify the approximate onset of leptin effects on the regulation of energy balance. We observed that male Lepob/ob mice started to exhibit increased body fat mass from postnatal day 13 (P13), whereas in females, the increase in adiposity began on P20. Daily leptin injections from P10 to P22 did not reduce the weight gain of WT mice. However, an acute leptin injection induced an anorexigenic response in 10-day-old C57BL/6 mice but not in 7-day-old mice. An age-dependent increase in the number of leptin receptor-expressing neurons and leptin-induced pSTAT3 cells was observed in the hypothalamus of P7, P10 and P16 mice. Leptin deficiency started to modulate the hypothalamic expression of transcripts involved in the regulation of metabolism between P7 and P12. Additionally, fasting-induced hypothalamic responses were prevented by leptin replacement in 10-day-old mice. Finally, 12-day-old males and females showed similar developmental timing of axonal projections of arcuate nucleus neurons in both WT and Lepob/ob mice. In summary, we provided a detailed characterization of the onset of leptin's effects on the regulation of energy balance. These findings contribute to the understanding of leptin functions during development.
Assuntos
Composição Corporal/efeitos dos fármacos , Metabolismo Energético/fisiologia , Leptina/metabolismo , Leptina/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Animais Lactentes , Composição Corporal/fisiologia , Peso Corporal , Feminino , Desenvolvimento Fetal , Privação de Alimentos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipotálamo/metabolismo , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Objectives. The onset of puberty in humans is followed by an increase in insulin resistance and this transient phenomenon decreases at the end of the puberty. However, the insulin resistance during puberty has not been described in mice. Thus, in the present study we performed a temporal characterization of the development of insulin resistance during puberty in male and female C57BL/6 mice.Methods. From the fourth week of life male (n=18) and female (n=32) C57BL/6 wild-type mice were weekly subjected to insulin tolerance tests until the seventh week of life. Blood glucose levels were determined using a glucose meter through samples collected from the tail tip. Vaginal opening was assessed daily in female mice. Preputial separation was determined in a subgroup of males.Results. We observed a transient increase in the area under the curve of the insulin tolerance tests and in basal glycemia in female mice at the time of vaginal opening (between the fourth and fifth week of life) compared with previous and subsequent weeks of pubertal development. In contrast, male mice show no changes in insulin sensitivity during puberty.Conclusions. Our findings demonstrate that the insulin resistance at puberty can also be observed in female mice and this peak occurs at the time of vaginal opening. Our temporal characterization can be used as a reference for future studies that aim to study glucose homeostasis during puberty in rodents.
Assuntos
Resistência à Insulina/fisiologia , Maturidade Sexual/fisiologia , Animais , Glicemia/análise , Feminino , Insulina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Caracteres Sexuais , Vagina/fisiologiaRESUMO
Previous studies indicate that leptin regulates the hypothalamic-pituitary-thyroid (HPT) axis via direct and indirect mechanisms. The indirect mechanism involves leptin action in pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurones. These cells innervate the paraventricular nucleus of the hypothalamus (PVH) where they modulate hypophysiotrophic thyrotrophin-releasing hormone (TRH)-producing neurones. The direct mechanism involves the expression of leptin receptor (LepR) in a subpopulation of PVH TRH neurones. However, to our knowledge, the existence of LepR in PVH TRH neurones of mice has not been clearly confirmed. Therefore, we investigated possible species-specific differences between rats and mice with respect to the mechanisms recruited by leptin to regulate the HPT axis. We observed that an acute leptin injection induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin-responsive cells, in 46.2 ± 8.0% of PVH proTRH immunoreactive neurones in rats. By contrast, an insignificant number of proTRH positive neurones in the mouse PVH co-expressed leptin-induced pSTAT3 or LepR. Similarly, central leptin injection increased the percentage of PVH proTRH neurones containing cAMP response element-binding protein phosphorylation in rats, but not in mice. We investigated the innervation of AgRP and POMC axons in the PVH and observed that rats exhibited a denser POMC innervation in the PVH compared to mice, whereas rats and mice showed similar density of AgRP axons in the PVH. In conclusion, rats and mice exhibit important species-specific differences in the direct and indirect mechanisms used by leptin to regulate the HPT axis.
Assuntos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Leptina/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Sistema Hipotálamo-Hipofisário/fisiologia , Leptina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Long-Evans , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Especificidade da Espécie , Glândula Tireoide/fisiologia , Hormônio Liberador de Tireotropina/metabolismoRESUMO
AIMS: Cholinergic neurons are distributed in brain areas containing growth hormone (GH)-responsive cells. We determined if cholinergic neurons are directly responsive to GH and the metabolic consequences of deleting the GH receptor (GHR) specifically in choline acetyltransferase (ChAT)-expressing cells. MAIN METHODS: Mice received an acute injection of GH to detect neurons co-expressing ChAT and phosphorylated STAT5 (pSTAT5), a well-established marker of GH-responsive cells. For the physiological studies, mice carrying ablation of GHR exclusively in ChAT-expressing cells were produced and possible changes in energy and glucose homeostasis were determined when consuming regular chow or high-fat diet (HFD). KEY FINDINGS: The majority of cholinergic neurons in the arcuate nucleus (60%) and dorsomedial nucleus (84%) of the hypothalamus are directly responsive to GH. Approximately 34% of pre-ganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus also exhibited GH-induced pSTAT5. GH-induced pSTAT5 in these ChAT neurons was absent in GHR ChAT knockout mice. Mice carrying ChAT-specific GHR deletion, either in chow or HFD, did not exhibit significant changes in body weight, body adiposity, lean body mass, food intake, energy expenditure, respiratory quotient, ambulatory activity, serum leptin levels, glucose tolerance, insulin sensitivity and metabolic responses to 2-deoxy-d-glucose. However, GHR deletion in ChAT neurons caused decreased hypothalamic Pomc mRNA levels in HFD mice. SIGNIFICANCE: Cholinergic neurons that regulate the metabolism are directly responsive to GH, although GHR signaling in these cells is not required for energy and glucose homeostasis. Thus, the physiological importance of GH action on cholinergic neurons still needs to be identified.
Assuntos
Neurônios Colinérgicos/metabolismo , Hormônio do Crescimento/metabolismo , Receptores da Somatotropina/metabolismo , Acetilcolina/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Dieta Hiperlipídica , Metabolismo Energético , Glucose/metabolismo , Hormônio do Crescimento/fisiologia , Hipotálamo/metabolismo , Resistência à Insulina/genética , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Somatotropina/genética , Fator de Transcrição STAT5/metabolismo , Nervo Vago/metabolismoRESUMO
The arcuate nucleus (ARH) is an important hypothalamic area for the homeostatic control of feeding and other metabolic functions. In the ARH, proopiomelanocortin- (POMC) and agouti-related peptide (AgRP)-expressing neurons play a key role in the central regulation of metabolism. These neurons are influenced by circulating factors, such as leptin and growth hormone (GH). The objective of the present study was to determine whether a direct action of GH on ARH neurons regulates the density of POMC and AgRP axonal projections to major postsynaptic targets. We studied POMC and AgRP axonal projections to the hypothalamic paraventricular (PVH), lateral (LHA) and dorsomedial (DMH) nuclei in leptin receptor (LepR)-deficient mice (Leprdb/db), GH-deficient mice (Ghrhrlit/lit) and in mice carrying specific ablations of GH receptor (GHR) either in LepR- or AgRP-expressing cells. Leprdb/db mice presented reduction in the density of POMC innervation to the PVH compared to wild-type and Ghrhrlit/lit mice. Additionally, both Leprdb/db and Ghrhrlit/lit mice showed reduced AgRP fiber density in the PVH, LHA and DMH. LepR GHR knockout mice showed decreased density of POMC innervation in the PVH and DMH, compared to control mice, whereas a reduction in the density of AgRP innervation was observed in all areas analyzed. Conversely, AgRP-specific ablation of GHR led to a significant reduction in AgRP projections to the PVH, LHA and DMH, without affecting POMC innervation. Our findings indicate that GH has direct trophic effects on the formation of POMC and AgRP axonal projections and provide additional evidence that GH regulates hypothalamic neurocircuits controlling energy homeostasis.
Assuntos
Núcleo Arqueado do Hipotálamo , Receptores da Somatotropina , Proteína Relacionada com Agouti/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptores da Somatotropina/genéticaRESUMO
Neurones expressing the melanin-concentrating hormone (MCH) can be found in the medial preoptic area (mPOA) and ventral aspects of the periventricular preoptic nucleus of rats by mid-to-late lactation and this expression disappears after weaning. The transitory expression of MCH in the preoptic area suggests a role for these neurones in the control of the end of lactation. However, the neurochemical identity of mPOA MCH neurones and the regulatory factors that control the transient MCH expression remain largely unknown, especially in the mouse. In the present study, we showed that mice also present the transitory expression of MCH in the mPOA at late lactation. mPOA MCH cells did not colocalise significantly with markers of GABAergic (VGAT), glutamatergic (VGLUT2 and VGLUT3) or dopaminergic (tyrosine hydroxylase) neurones. mPOA MCH cells also did not express Kiss1 or oxytocin. By contrast, approximately 70% and 90% of mPOA MCH neurones colocalised with oestrogen receptor α and prolactin-induced phosphorylated signal transducer and activator of transcription 5 (STAT5), respectively. Finally, we demonstrated that the number of MCH neurones in the mPOA is significantly higher in females during the first lactation, compared to mice on the second lactation or pregnant mice during the first lactation or brain-specific STAT5 knockout mice during the first lactation. In summary, our findings indicate that MCH neurones in the mPOA of lactating mice are sensitive to oestrogens and prolactin. Thus, mPOA MCH expression is possibly influenced by hormonal variations. Furthermore, the STAT5 signalling pathway is likely involved in the regulation of MCH expression in the mPOA of lactating mice.
Assuntos
Hormônios Hipotalâmicos/metabolismo , Lactação/metabolismo , Melaninas/metabolismo , Neurônios/patologia , Hormônios Hipofisários/metabolismo , Área Pré-Óptica/metabolismo , Animais , Feminino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT5/genéticaRESUMO
AgRP neurons are important players in the control of energy homeostasis and are responsive to several hormones. In addition, STAT5 signalling in the brain, which is activated by metabolic hormones and growth factors, modulates food intake, body fat and glucose homeostasis. Given that, and the absence of studies that describe STAT5 function in AgRP cells, the present study investigated the metabolic effects of Stat5a/b gene ablation in these neurons. We observed that STAT5 signalling in AgRP neurons regulates body fat in female mice. However, male and female STAT5-knockout mice did not exhibit altered food intake, energy expenditure or glucose homeostasis compared to control mice. The counter-regulatory response or glucoprivic hyperphagia induced by 2-deoxy-d-glucose treatment were also not affected by AgRP-specific STAT5 ablation. However, under 60% food restriction, AgRP STAT5-knockout mice had a blunted upregulation of hypothalamic Agrp mRNA expression and corticosterone serum levels compared to control mice, suggesting a possible role for STAT5 in AgRP neurons for neuroendocrine adaptations to food restriction. Interestingly, ad libitum fed knockout male mice had reduced Pomc and Ucp-1 mRNA expression compared to control group. Taken together, these results suggest that STAT5 signalling in AgRP neurons regulates body adiposity in female mice, as well as some neuroendocrine adaptations to food restriction.
Assuntos
Adaptação Fisiológica/fisiologia , Adiposidade/fisiologia , Proteína Relacionada com Agouti/metabolismo , Metabolismo Energético/fisiologia , Neurônios/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Ingestão de Alimentos/fisiologia , Feminino , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Desacopladora 1/metabolismo , Regulação para Cima/fisiologiaRESUMO
Several metabolic and behavioral adaptations that emerge during pregnancy remain present after weaning. Thus, reproductive experience causes long-lasting metabolic programming, particularly in the brain. However, the isolate effects of pregnancy or lactation and the molecular mechanisms involved in these long-term modifications are currently unknown. In the current study, we investigated the role of brain signal transducer and activator of transcription-5 (STAT5), a key transcription factor recruited by hormones highly secreted during gestation or lactation, for the long-term adaptations induced by reproductive experience. In control mice, pregnancy followed by lactation led to increased body adiposity and reduced ambulatory activity later in life. Additionally, pregnancy+lactation induced long-term epigenetic modifications in the brain: we observed upregulation in hypothalamic expression of histone deacetylases and reduced numbers of neurons with histone H3 acetylation in the paraventricular, arcuate, and ventromedial nuclei. Remarkably, brain-specific STAT5 ablation prevented all metabolic and epigenetic changes observed in reproductively experienced control female mice. Nonetheless, brain-specific STAT5 knockout (KO) mice that had the experience of pregnancy but did not lactate showed increased body weight and reduced energy expenditure later in life, whereas pregnancy KO and pregnancy+lactation KO mice exhibited improved insulin sensitivity compared with virgin KO mice. In summary, lactation is necessary for the long-lasting metabolic effects observed in reproductively experienced female mice. In addition, epigenetic mechanisms involving histone acetylation in neuronal populations related to energy balance regulation are possibly associated with these long-term consequences. Finally, our findings highlighted the key role played by brain STAT5 signaling for the chronic metabolic and epigenetic changes induced by pregnancy and lactation.
Assuntos
Hipotálamo/metabolismo , Lactação , Prenhez/metabolismo , Fator de Transcrição STAT5/metabolismo , Adiposidade , Animais , Epigênese Genética , Feminino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Gravidez , Distribuição AleatóriaRESUMO
Several hypothalamic neuronal populations are directly responsive to growth hormone (GH) and central GH action regulates glucose and energy homeostasis. However, the potential role of GH signaling in proopiomelanocortin (POMC) neurons has not been studied yet. Thus, we investigated whether POMC neurons are responsive to GH and if ablation of GH receptor (GHR) or STAT5 in POMC cells leads to metabolic imbalances. Approximately 60% of POMC neurons of the arcuate nucleus exhibited STAT5 phosphorylation after intracerebroventricular GH injection. Ablation of GHR or STAT5 in POMC cells did not affect energy or glucose homeostasis. However, glucoprivic hyperphagia was blunted in male and female GHR knockout mice, and in male POMC-specific STAT5 knockout mice. Additionally, the absence of GHR in POMC neurons decreased glycemia during prolonged food restriction in male mice. Thus, GH action in POMC neurons regulates glucoprivic hyperphagia as well as blood glucose levels during prolonged food restriction.
Assuntos
Proteínas de Transporte/fisiologia , Glucose/metabolismo , Hiperfagia/patologia , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Fator de Transcrição STAT5/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Feminino , Hiperfagia/metabolismo , Masculino , Camundongos , Camundongos KnockoutRESUMO
The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)-expressing neurons, in leptin receptor (LepR)-expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other "gestational hormones" to prepare the maternal organism for the metabolic demands of the offspring.
Assuntos
Hormônio do Crescimento/fisiologia , Prenhez/metabolismo , Adiposidade/genética , Animais , Química Encefálica/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Ingestão de Alimentos , Feminino , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Resistência à Insulina/genética , Leptina/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Gravidez , Receptores para Leptina/metabolismoRESUMO
Growth hormone (GH) is secreted during hypoglycemia, and GH-responsive neurons are found in brain areas containing glucose-sensing neurons that regulate the counter-regulatory response (CRR). However, whether GH modulates the CRR to hypoglycemia via specific neuronal populations is currently unknown. Mice carrying ablation of GH receptor (GHR) either in leptin receptor (LepR)- or steroidogenic factor-1 (SF1)-expressing cells were studied. We also investigated the importance of signal transducer and activator of transcription 5 (STAT5) signaling in SF1 cells for the CRR. GHR ablation in LepR cells led to impaired capacity to recover from insulin-induced hypoglycemia and to a blunted CRR caused by 2-deoxy-d-glucose (2DG) administration. GHR inactivation in SF1 cells, which include ventromedial hypothalamic neurons, also attenuated the CRR. The reduced CRR was prevented by parasympathetic blockers. Additionally, infusion of 2DG produced an abnormal hyperactivity of parasympathetic preganglionic neurons, whereas the 2DG-induced activation of anterior bed nucleus of the stria terminalis neurons was reduced in mice without GHR in SF1 cells. Mice carrying ablation of Stat5a/b genes in SF1 cells showed no defects in the CRR. In summary, GHR expression in SF1 cells is required for a normal CRR, and these effects are largely independent of STAT5 pathway.-Furigo, I. C., de Souza, G. O., Teixeira, P. D. S., Guadagnini, D., Frazão, R., List, E. O., Kopchick, J. J., Prada, P. O., Donato, J., Jr. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons.
Assuntos
Hormônio do Crescimento/farmacologia , Hipoglicemia/tratamento farmacológico , Hipotálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Desoxiglucose/farmacologia , Hipoglicemia/fisiopatologia , Hipotálamo/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Receptores da Somatotropina/genética , Receptores da Somatotropina/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismoRESUMO
The original version of this Article contained an error in the spelling of the author J. Donato Jr, which was incorrectly given as Donato J. Jr. This has now been corrected in both the PDF and HTML versions of the Article.
RESUMO
Weight loss triggers important metabolic responses to conserve energy, especially via the fall in leptin levels. Consequently, weight loss becomes increasingly difficult with weight regain commonly occurring in most dieters. Here we show that central growth hormone (GH) signaling also promotes neuroendocrine adaptations during food deprivation. GH activates agouti-related protein (AgRP) neurons and GH receptor (GHR) ablation in AgRP cells mitigates highly characteristic hypothalamic and metabolic adaptations induced by weight loss. Thus, the capacity of mice carrying an AgRP-specific GHR ablation to save energy during food deprivation is impaired, leading to increased fat loss. Additionally, administration of a clinically available GHR antagonist (pegvisomant) attenuates the fall of whole-body energy expenditure of food-deprived mice, similarly as seen by leptin treatment. Our findings indicate GH as a starvation signal that alerts the brain about energy deficiency, triggering key adaptive responses to conserve limited fuel stores.
Assuntos
Proteína Relacionada com Agouti/metabolismo , Receptores da Somatotropina/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/farmacologia , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Somatotropina/genética , Redução de Peso/efeitos dos fármacosRESUMO
Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus; however, the mechanism of action of the antidiabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control, but it also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the current study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, and increased insulin sensitivity in the liver and skeletal muscle compared with vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Because G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising therapeutic approach to control blood glucose levels in individuals with insulin resistance.