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Provision of amino acids to the liver is instrumental for gluconeogenesis while it requires safe disposal of the amino group. The mitochondrial enzyme glutamate dehydrogenase (GDH) is central for hepatic ammonia detoxification by deaminating excessive amino acids toward ureagenesis and preventing hyperammonemia. The present study investigated the early adaptive responses to changes in dietary protein intake in control mice and liver-specific GDH KO mice (Hep-Glud1-/-). Mice were fed chow diets with a wide coverage of protein contents; i.e., suboptimal 10%, standard 20%, over optimal 30%, and high 45% protein diets; switched every 4 days. Metabolic adaptations of the mice were assessed in calorimetric chambers before tissue collection and analyses. Hep-Glud1-/- mice exhibited impaired alanine induced gluconeogenesis and constitutive hyperammonemia. The expression and activity of GDH in liver lysates were not significantly changed by the different diets. However, applying an in situ redox-sensitive assay on cryopreserved tissue sections revealed higher hepatic GDH activity in mice fed the high-protein diets. On the same section series, immunohistochemistry provided corresponding mapping of the GDH expression. Cosinor analysis from calorimetric chambers showed that the circadian rhythm of food intake and energy expenditure was altered in Hep-Glud1-/- mice. In control mice, energy expenditure shifted from carbohydrate to amino acid oxidation when diet was switched to high protein content. This shift was impaired in Hep-Glud1-/- mice and consequently the spontaneous physical activity was markedly reduced in GDH KO mice. These data highlight the central role of liver GDH in the energy balance adaptation to dietary proteins.
Assuntos
Proteínas Alimentares , Metabolismo Energético , Glutamato Desidrogenase , Fígado , Animais , Masculino , Camundongos , Proteínas Alimentares/metabolismo , Gluconeogênese , Glutamato Desidrogenase/metabolismo , Glutamato Desidrogenase/genética , Fígado/metabolismo , Camundongos Knockout , Nitrogênio/metabolismoRESUMO
Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood.
Assuntos
Encéfalo , Leptina , Neurogênese , Receptores para Leptina , Animais , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Camundongos , Encéfalo/metabolismo , Leptina/deficiência , Leptina/metabolismo , Neurogênese/fisiologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/genética , Atrofia/patologiaRESUMO
It is increasingly recognized that sleep disturbances and Alzheimer's disease (AD) share a bidirectional relationship. AD patients exhibit sleep problems and alterations in the regulation of circadian rhythms; conversely, poor quality of sleep increases the risk of development of AD. The aim of the current study was to determine whether chronic sleep restriction potentiates the brain impact of amyloid-ß oligomers (AßOs), toxins that build up in AD brains and are thought to underlie synapse damage and memory impairment. We further investigated whether alterations in levels of pro-inflammatory mediators could play a role in memory impairment in sleep-restricted mice. We found that a single intracerebroventricular (i.c.v.) infusion of AßOs disturbed sleep pattern in mice. Conversely, chronically sleep-restricted mice exhibited higher brain expression of pro-inflammatory mediators, reductions in levels of pre- and post-synaptic marker proteins, and exhibited increased susceptibility to the impact of i.c.v. infusion of a sub-toxic dose of AßOs (1pmol) on performance in the novel object recognition memory task. Sleep-restricted mice further exhibited an increase in brain TNF-α levels in response to AßOs. Interestingly, memory impairment in sleep-restricted AßO-infused mice was prevented by treatment with the TNF-α neutralizing monoclonal antibody, infliximab. Results substantiate the notion of a dual relationship between sleep and AD, whereby AßOs disrupt sleep/wake patterns and chronic sleep restriction increases brain vulnerability to AßOs, and point to a key role of brain inflammation in increased susceptibility to AßOs in sleep-restricted mice.
Assuntos
Peptídeos beta-Amiloides/administração & dosagem , Disfunção Cognitiva/fisiopatologia , Encefalite/fisiopatologia , Privação do Sono/patologia , Privação do Sono/fisiopatologia , Sinapses/patologia , Animais , Disfunção Cognitiva/etiologia , Encefalite/etiologia , Infliximab/administração & dosagem , Masculino , Camundongos , Privação do Sono/induzido quimicamenteRESUMO
Prolactin and placental lactogens control mammary development and lactation as well as play an important role in maternal behaviors. However, the molecular mechanisms in the brain responsible for this regulation remain largely unknown. Therefore, the present study investigated whether Signal Transducer and Activator of Transcription 5 (STAT5) signaling in the brain, the key transcriptional factor recruited by prolactin receptor and other hormones, is required for postpartum maternal behavior, maintenance of lactation and offspring growth. Neuronal ablation of STAT5 impaired the control of prolactin secretion and reduced the hypothalamic expression of suppressors of cytokine signaling (i.e., SOCS3 and CISH). In addition, neuronal STAT5 deletion attenuated the hyperphagia commonly observed during lactation by decreasing the hypothalamic expression of orexigenic neurotransmitters such as the neuropeptide Y and agouti-related protein. The lower food intake of lactating neuron-specific STAT5 knockout females resulted in reduced milk production and offspring growth. Unexpectedly, postpartum maternal behavior expression was not impaired in neuron-specific STAT5 knockout females. On the contrary, the latency to retrieve and group the pups into the nest was reduced in mutant dams. Finally, we demonstrated that approximately 30% of recorded neurons in the medial preoptic area were acutely depolarized by prolactin suggesting that fast STAT5-independent signaling pathways may be involved in the regulation of maternal behaviors. Overall, our results revealed important information about the molecular mechanisms recruited by hormones to orchestrate the activation of neural circuitries engaged in the induction of maternal care.
Assuntos
Lactação/fisiologia , Comportamento Materno/fisiologia , Neurônios/fisiologia , Período Pós-Parto/psicologia , Fator de Transcrição STAT5/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Feminino , Expressão Gênica/fisiologia , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Área Pré-Óptica/metabolismo , Prolactina/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Rodent models raised at environmental temperatures of 21-22 °C are increasingly switched to thermoneutral housing conditions in adulthood to better capture human physiology. We quantified the developmental effects of rearing mice at an ambient temperature of 22 °C vs. 30 °C on metabolic responses to cold and high fat diet (HFD) in adulthood. METHODS: Mice were reared from birth to 8 weeks of age at 22 °C or 30 °C, when they were acclimated to single housing at the same temperature for 2-3 weeks in indirect calorimetry cages. Energy expenditure attributable to basal metabolic rate, physical activity, thermic effect of food, and adaptive cold- or diet-induced thermogenesis was calculated. Responses to cooling were evaluated by decreasing the ambient temperature from 22 °C to 14 °C, while responses to HFD feeding were assessed at 30 °C. Influences of rearing temperature on thermogenic responses that emerge over hours, days and weeks were assessed by maintaining mice in the indirect calorimetry cages throughout the study. RESULTS: At an ambient temperature of 22 °C, total energy expenditure (TEE) was 12-16% higher in mice reared at 22 °C as compared to 30 °C. Rearing temperature had no effect on responses in the first hours or week of the 14 °C challenge. Differences emerged in the third week, when TEE increased an additional 10% in mice reared at 22 °C, but mice reared at 30 °C could not sustain this level of cold-induced thermogenesis. Rearing temperature only affected responses to HFD during the first week, due to differences in the timing but not the strength of metabolic adaptations. CONCLUSION: Rearing at 22 °C does not have a lasting effect on metabolic adaptations to HFD at thermoneutrality, but it programs an enhanced capacity to respond to chronic cold challenges in adulthood. These findings highlight the need to consider rearing temperature when using mice to model cold-induced thermogenesis.
Assuntos
Temperatura Baixa , Dieta Hiperlipídica , Humanos , Camundongos , Animais , Lactente , Temperatura , Dieta Hiperlipídica/efeitos adversos , Termogênese/fisiologia , Metabolismo BasalRESUMO
Obesity is defined as abnormal or excessive fat accumulation that may impair health and is a risk factor for developing other diseases, such as type 2 diabetes and cardiovascular disorder. Obesity is also associated with structural and functional alterations in the brain, and this condition has been shown to increase the risk of Alzheimer's disease. However, while obesity has been associated with neurodegenerative processes, its impact on brain cell composition remains to be determined. In the current study, we used the isotropic fractionator method to determine the absolute composition of neuronal and non-neuronal cells in different brain regions of the genetic mouse models of obesity Lepob/ob and LepRNull/Null . Our results show that 10- to 12-month-old female Lepob/ob and LepRNull/Null mice have reduced neuronal number and density in the hippocampus compared to C57BL/6 wild-type mice. Furthermore, LepRNull/Null mice have increased density of non-neuronal cells, mainly glial cells, in the hippocampus, frontal cortex and hypothalamus compared to wild-type or Lepob/ob mice, indicating enhanced inflammatory responses in different brain regions of the LepRNull/Null model. Collectively, our findings suggest that obesity might cause changes in brain cell composition that are associated with neurodegenerative and inflammatory processes in different brain regions of female mice.
RESUMO
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
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
The suppressors of cytokine signaling (SOCS) are a group of eight proteins responsible for preventing excessive cytokine signaling. Among this protein family, SOCS3 has received special attention. SOCS3 expression is important to control certain allergy autoimmune diseases. Furthermore, SOCS3 expression is elevated in obesity and it is involved in the inhibition of leptin and insulin signaling, two important hormones involved in the control of energy metabolism. Therefore, increased SOCS3 expression in obese individuals is associated with several metabolic disorders, including reduced energy expenditure, increased food intake and adiposity, and insulin and leptin resistance. In addition, recent studies found that SOCS3 expression regulates energy and glucose homeostasis in several metabolic conditions, such as pregnancy, caloric restriction, and refeeding. Importantly, attenuation of SOCS3 expression in most cases improves leptin and insulin sensitivity, leading to beneficial metabolic effects. This review aims to discuss the role of SOCS3 in the control of blood glucose levels as well as in energy homeostasis. The development of pharmacological compounds to inhibit SOCS3 activity and/or expression may represent a promising therapeutic approach to treat type 2 diabetes mellitus, obesity, and other metabolic imbalances.
Assuntos
Doenças Metabólicas/tratamento farmacológico , Terapia de Alvo Molecular/tendências , Proteína 3 Supressora da Sinalização de Citocinas/antagonistas & inibidores , Proteína 3 Supressora da Sinalização de Citocinas/fisiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Obesidade/tratamento farmacológico , Gravidez , Complicações na Gravidez/tratamento farmacológicoRESUMO
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
Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the fourth or tenth week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems.
Assuntos
Envelhecimento/genética , Regulação da Expressão Gênica no Desenvolvimento , Leptina/genética , Obesidade/genética , Receptores para Leptina/genética , Envelhecimento/metabolismo , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/crescimento & desenvolvimento , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Metabolismo Energético/genética , Feminino , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Gônadas/patologia , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Hipotálamo/patologia , Leptina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Obesidade/metabolismo , Obesidade/patologia , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Hormônio Liberador de Prolactina/genética , Hormônio Liberador de Prolactina/metabolismo , Receptores para Leptina/deficiência , Transdução de SinaisRESUMO
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.
Assuntos
Bromocriptina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Prolactina/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Obesos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismoRESUMO
Several metabolic adaptations emerge during pregnancy and continue through lactation, including increases in food intake and body weight, as well as insulin and leptin resistance. These maternal adaptations are thought to play a role in offspring viability and success. Using a model of attenuated maternal metabolic adaptations induced by ablation of the Socs3 gene in leptin receptor expressing cells (SOCS3 KO mice), our study aimed to investigate whether maternal metabolic changes are required for normal offspring development, and if their absence causes metabolic imbalances in adulthood. The litters were subjected to a cross-fostering experimental design to distinguish the prenatal and postnatal effects caused by maternal metabolic adaptations. Males either born or raised by SOCS3 KO mice showed reduced body weight until 8 weeks of life. Both adult males and females born or raised by SOCS3 KO mice also had lower body adiposity. Despite that, no significant changes in energy expenditure, glucose tolerance or insulin resistance were observed. However, males either born or raised by SOCS3 KO mice showed reduced brain mass in adulthood. Furthermore, animals born from SOCS3 KO mice also had lower proopiomelanocortin fiber density in the paraventricular nucleus of the hypothalamus. In conclusion, these findings indicate that the commonly observed metabolic changes in pregnancy and lactation are necessary for normal offspring growth and brain development.
Assuntos
Adaptação Fisiológica , Encéfalo/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Adiposidade , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Metabolismo Energético , Feminino , Resistência à Insulina , Masculino , Camundongos , Gravidez , Pró-Opiomelanocortina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Fatores Sexuais , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
The signal transducer and activator of transcription 5 (STAT5) is a transcription factor recruited by numerous cytokines. STAT5 is important for several physiological functions, including body and tissue growth, mammary gland development, immune system and lipid metabolism. However, the role of STAT5 signaling for brain functions is still poorly investigated, especially regarding cognitive aspects. Therefore, the objective of the present study was to investigate whether brain STAT5 signaling modulates learning and memory formation. For this purpose, brain-specific STAT5 knockout (STAT5 KO) mice were studied in well-established memory tests. Initially, we confirmed a robust reduction in STAT5a and STAT5b mRNA levels in different brain structures of STAT5 KO mice. STAT5 KO mice showed no significant alterations in metabolism, growth, somatotropic axis and spontaneous locomotor activity. In contrast, brain-specific STAT5 ablation impaired learning and memory formation in the novel object recognition, Barnes maze and contextual fear conditioning tests. To unravel possible mechanisms that might underlie the memory deficits of STAT5 KO mice, we assessed neurogenesis in the hippocampus, but no significant differences were observed between groups. On the other hand, reduced insulin-like growth factor-1 (IGF-1) mRNA expression was found in the hippocampus and hypothalamus of STAT5 KO mice. These findings collectively indicate that brain STAT5 signaling is required to attain normal learning and memory. Therefore, STAT5 is an important downstream cellular mechanism shared by several cytokines to regulate cognitive functions.
Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Aprendizagem em Labirinto/fisiologia , Reconhecimento Psicológico/fisiologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/fisiologia , Animais , Condicionamento Psicológico , Citocinas/metabolismo , Comportamento Exploratório/fisiologia , Medo/psicologia , Fator de Crescimento Insulin-Like I/metabolismo , Deficiências da Aprendizagem/genética , Camundongos , Camundongos Transgênicos , Nestina/genética , Nestina/metabolismo , Neurogênese/genética , RNA Mensageiro/metabolismo , Tempo de Reação/genética , Fator de Transcrição STAT5/genéticaRESUMO
Leptin is a master regulator of energy balance and body adiposity. Additionally, leptin exerts important control on glucose homeostasis, thermogenesis, autonomic nervous system and neuroendocrine axes. In metabolic diseases, such as obesity and diabetes mellitus, leptin signaling may be compromised, indicating the important role of this hormone in the etiology and pathophysiological manifestations of these conditions. In the present manuscript, we reviewed important concepts of leptin signaling, as well as about the effects of leptin on several biologic functions. We also discussed the possible therapeutic use of leptin administration and how our current obesogenic environment contributes to the development of leptin resistance. Our objective was to provide a comprehensive and state-of-the-art review about the importance of leptin to maintain the homeostasis and during pathological conditions.
RESUMO
Previous studies have shown that leptin resistance is a key feature that leads to gestational metabolic adaptions. We hypothesized that leptin sensitivity in the ventromedial nucleus of the hypothalamus (VMH) plays a critical role regulating gestational metabolic changes. In the present study, we generated a mouse model carrying ablation of the suppressor of cytokine signaling 3 (SOCS3) in steroidogenic factor-1 (SF1) cells, which include the VMH, in order to investigate whether increased leptin sensitivity in this neuronal population prevents at least part of the metabolic changes typically observed during gestation and lactation. As predicted by the inhibitory effects of SOCS3 in leptin signaling, pregnant SF1 SOCS3 KO mice exhibited increased leptin sensitivity in the VMH, since an acute leptin injection induced a 95% increase in the STAT3 phosphorylation in this nucleus, compared to control animals (pâ¯=â¯0.02). Despite that, SF1 SOCS3 KO mice showed similar weight gain, food intake, hypothalamic neuropeptide expression and serum leptin levels during pregnancy compared to control littermates. Unexpectedly, SF1 SOCS3 KO mice exhibited glucose intolerance during pregnancy. SF1 SOCS3 KO mice also presented a lower body weight (-3%; pâ¯<â¯0.05) during mid and late lactation, although food intake, litter size and offspring growth were not affected. Our findings suggest that increased leptin sensitivity in the VMH causes modest metabolic effects and is not sufficient to prevent major metabolic adaptations of pregnancy and lactation.
Assuntos
Lactação/metabolismo , Neurônios/metabolismo , Gravidez/metabolismo , Fator Esteroidogênico 1/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/deficiência , Adiposidade/efeitos dos fármacos , Adiposidade/genética , Animais , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Teste de Tolerância a Glucose , Insulina/metabolismo , Lactação/efeitos dos fármacos , Leptina/farmacologia , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fator Esteroidogênico 1/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Núcleo Hipotalâmico Ventromedial/citologiaRESUMO
Many hormones/cytokines are secreted in response to exercise and cytokine signaling may play a pivotal role in the training adaptations. To investigate the importance of cytokine signaling during vertical ladder climbing, a resistance exercise model, we produced mice lacking SOCS3 protein exclusively in steroidogenic factor-1 (SF1) cells (SF1 Socs3 KO mice). SF1 expression is found in steroidogenic cells of the adrenal cortex and gonads, as well as in neurons of the ventromedial nucleus of the hypothalamus. Histological markers of the fetal adrenal zone (or X-zone in rodents) were still present in adult males and postpartum SF1 Socs3 KO females, suggesting a previously unrecognized effect of SOCS3 on the terminal differentiation of the adrenal gland. This change led to a distinct distribution of lipid droplets along the adrenal cortex. Under basal conditions, adult SF1 Socs3 KO mice exhibited similar adrenal weight, and plasma ACTH and corticosterone concentrations. Nonetheless, SF1 Socs3 KO mice exhibited a blunted ACTH-induced corticosterone secretion. The overall metabolic responses induced by resistance training remained unaffected in SF1 Socs3 KO mice, including changes in body adiposity, glucose tolerance and energy expenditure. However, training performance and glucose control during intense resistance exercise were impaired in SF1 Socs3 KO mice. Furthermore, a reduced counter-regulatory response to 2-deoxy-d-glucose was observed in mutant mice. These findings revealed a novel participation of SOCS3 regulating several endocrine and metabolic aspects. Therefore, cytokine signaling in SF1 cells exerts an important role to sustain training performance possibly by promoting the necessary metabolic adjustments during exercise.
Assuntos
Diferenciação Celular/fisiologia , Fator Esteroidogênico 1/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Adiposidade/genética , Adiposidade/fisiologia , Glândulas Suprarrenais/metabolismo , Animais , Diferenciação Celular/genética , Corticosterona/metabolismo , Desoxiglucose/metabolismo , Feminino , Masculino , Camundongos , Camundongos Knockout , Hipófise/metabolismo , Fator Esteroidogênico 1/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Testículo/metabolismo , Testosterona/metabolismoRESUMO
Several growth factors and cytokines recruit the signal transducer and activator of transcription 5 (STAT5) signaling pathway to control cell proliferation, differentiation and apoptosis. Nonetheless, the importance of this transcription factor for brain functions is still poorly understood. Because some STAT5-inducing hormones, such as prolactin and leptin, act in the brain to regulate the expression of motivated behaviors, this signaling pathway is likely involved in behavioral modulation. Therefore, the objective of the present review was to summarize and discuss the available data regarding the possible role of central STAT5 signaling in the regulation of brain functions, especially on behavioral control. We discussed studies that investigated the importance of STAT5 signaling in the regulation of maternal and feeding behaviors. Additionally, we highlighted other behaviors that could be potentially affected by STAT5 signaling. This knowledge may help to understand how motivated behaviors are regulated at the cellular level.
Assuntos
Comportamento , Encéfalo/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Animais , Humanos , Modelos BiológicosRESUMO
Obesity reduces breastfeeding success and lactation performance in women. However, the mechanisms involved are not entirely understood. In the present study, female C57BL/6 mice were chronically exposed to a high-fat diet to induce obesity and subsequently exhibited impaired offspring viability (only 15% survival rate), milk production (33% reduction), mammopoiesis (one-third of the glandular area compared to control animals) and postpartum maternal behaviors (higher latency to retrieving and grouping the pups). Reproductive experience attenuated these defects. Diet-induced obese mice exhibited high basal pSTAT5 levels in the mammary tissue and hypothalamus, and an acute prolactin stimulus was unable to further increase pSTAT5 levels above basal levels. In contrast, genetically obese leptin-deficient females showed normal prolactin responsiveness. Additionally, we identified the expression of leptin receptors specifically in basal/myoepithelial cells of the mouse mammary gland. Finally, high-fat diet females exhibited altered mRNA levels of ERBB4 and NRG1, suggesting that obesity may involve disturbances to mammary gland paracrine circuits that are critical in the control of luminal progenitor function and lactation. In summary, our findings indicate that high leptin levels are a possible cause of the peripheral and central prolactin resistance observed in obese mice which leads to impaired lactation performance.
Assuntos
Lactação/fisiologia , Leptina/metabolismo , Glândulas Mamárias Animais/metabolismo , Obesidade/metabolismo , Prolactina/metabolismo , Animais , Dieta Hiperlipídica , Feminino , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neuregulina-1/genética , RNA Mensageiro/biossíntese , Receptor ErbB-4/genética , Fator de Transcrição STAT5/metabolismoRESUMO
Weight regain frequently follows interventions that reduce body weight, leading to a failure in long-term obesity treatment. Inhibitory proteins of the leptin signaling pathway, such as the suppressor of cytokine signaling 3 (SOCS3), have been studied in conditions that predispose animals to obesity. However, whether SOCS3 modulates postrestriction hyperphagia and weight regain remains unknown. Mice lacking SOCS3 protein specifically in leptin receptor (LepR)-expressing cells (LepR SOCS3 knockout [KO]) were generated and studied in fasting and refeeding conditions. LepR SOCS3 KO mice exhibited increased leptin sensitivity in the hypothalamus. Notably, LepR SOCS3 KO males and females showed attenuated food intake and weight regain after 48 hours of fasting. Postrestriction hyperleptinemia was also prevented in LepR SOCS3 KO mice. Next, we studied possible mechanisms and neural circuits involved in the SOCS3 effects. SOCS3 deletion did not prevent fasting- or refeeding-induced c-Fos expression in the arcuate nucleus of the hypothalamus (ARH) nor fasting-induced increased excitability of ARH LepR-expressing cells. On the other hand, SOCS3 ablation reduced the mRNA levels of hypothalamic orexigenic neuropeptides during fasting (neuropeptide Y, agouti-related protein, orexin, and melanin-concentrating hormone). In summary, our findings suggest that increased leptin sensitivity contributes to the maintenance of a reduced body weight after food deprivation. In addition, the attenuated postrestriction food intake observed in mutant mice was not explained by fasting-induced changes in the activity of ARH neurons but exclusively by a lower transcription of orexigenic neuropeptides during fasting. These results indicate a partial dissociation between the regulation of neuronal activity and gene expression in ARH LepR-expressing cells.