RESUMO
Polycyclic aromatic hydrocarbons (PAHs) are naturally occurring environmental pollutants that may contribute to obesity in the adult population. To investigate the relationship between the urinary concentrations of PAH metabolites and adult obesity among the US population, the National Health and Nutritional Examination Survey (NHANES, 2003-2016) was used as a data source for this study. As many as 4464 participants in the NHANES 2003-2016 were included in the final analyses. We used logistic regression to look at the link between urinary PAH metabolites and obesity, using odds ratios (ORs) and 95% confidence intervals (CIs). The study sample comprised 4464 individuals aged ≥18 years, 2199 were male and 2265 were female. The study characteristics for four different quartiles were analyzed, and the average ages of the four urinary PAH quartiles were 49.61 ± 20.01, 46.63 ± 20.33, 44.28 ± 19.19, and 43.27 ± 17.68 years, respectively. In the quartile analysis of all participants, the third quartile was significantly associated with an increased prevalence of obesity (OR = 1.33, 95% CI = 1.12-1.59) with p-values <.05. In addition, females, but not males, had a strong link between the second, third, and fourth quartiles of urinary PAH and a higher risk of obesity (OR = 1.27, 95% CI = 1.00-1.61; OR = 1.52, 95% CI = 1.19-1.94; and OR = 1.39, 95% CI = 1.09-1.78). In conclusion, the study observed that urinary PAH metabolites were associated with the prevalence of obesity among the US population.
RESUMO
Objective: Kisspeptin, encoded by the Kiss1 gene, ties puberty and fertility to energy status; however, the metabolic factors that control Kiss1-expressing cells need to be clarified. Methods: To evaluate the impact of IGF-1 on the metabolic and reproductive functions of kisspeptin producing cells, we created mice with IGF-1 receptor deletion driven by the Kiss1 promoter (IGF1RKiss1 mice). Previous studies have shown IGF-1 and insulin can bind to each other's receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we also generated mice with simultaneous deletion of the IGF1R and insulin receptor (IR) in Kiss1-expressing cells (IGF1R/IRKiss1 mice). Results: Loss of IGF1R in Kiss1 cells caused stunted body length. In addition, female IGF1RKiss1 mice displayed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was linked to higher proopiomelanocortin (POMC) expression and heightened brown adipose tissue (BAT) thermogenesis. Male IGF1RKiss1 mice had mild changes in metabolic functions. Moreover, IGF1RKiss1 mice of both sexes experienced delayed puberty. Notably, male IGF1RKiss1 mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R in Kiss1-expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IRKiss1 mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR in Kiss1-expressing cells together regulate body composition and glucose homeostasis. Conclusions: Overall, our study shows that IGF1R and IR in Kiss1 have cooperative roles in body length, metabolism, and reproduction.
RESUMO
Flavonoids derived from plants offer a broad spectrum of therapeutic potential for addressing metabolic syndrome, particularly diabetes mellitus (DM), a prevalent non-communicable disease. Hyperglycemia in DM is a known risk factor for cardiovascular diseases (CVDs), which substantially impact global mortality rates. This review examines the potential effects of naringin, a citrus flavonoid, on both DM and its associated cardiovascular complications, including conditions like diabetic cardiomyopathy. The safety profile of naringin is summarized based on various pre-clinical studies. The data for this review was gathered from diverse electronic databases, including Medline, PubMed, ScienceDirect, SpringerLink, Google Scholar, and Emerald Insight. Multiple pre-clinical studies have demonstrated that naringin exerts hypoglycemic and cardioprotective effects by targeting various vascular mechanisms. Specifically, research indicates that naringin down-regulates the renin-angiotensin and oxidative stress systems while concurrently upregulating ß-cell and immune system functions. Clinical trial outcomes also support the therapeutic potential of naringin in managing hyperglycemic states and associated cardiovascular issues. Moreover, toxicity studies have confirmed the safety of naringin in animal models, suggesting its potential for safe administration in humans. In conclusion, naringin emerges as a promising natural candidate for both antidiabetic and cardioprotective purposes, offering potential improvements in health outcomes. While naringin presents a new avenue for therapies targeting DM and CVDs, additional controlled and long-term clinical trials are necessary to validate its efficacy and safety for human use.
Assuntos
Cardiotônicos , Flavanonas , Hipoglicemiantes , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Humanos , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
Methotrexate (MTX)-induced intestinal mucositis (IM) is a common side effect in cancer treatment that impairs the immune system and gut microbes, resulting in loss of mucosal integrity and gut barrier dysfunction. The quality of life and outcomes of treatment are compromised by IM. The present study was designed to investigate the mucoprotective potential of the benzimidazole derivative N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide (B8) on MTX-induced IM in mice. IM was induced by a single dose of MTX in mice and assessed by physical manifestations as well as biochemical, oxidative, histological, and inflammatory parameters. B8 (1, 3, 9 mg/kg) significantly reduced diarrhea score, mitigated weight loss, increased feed intake and, survival rate in a dose-dependent manner. Notably, B8 exhibited a mucoprotective effect evident through the mitigation of villus atrophy, crypt hypoplasia, diminished crypt mitotic figures, mucin depletion, and oxidative stress markers (GSH, SOD, MDA, and catalase concentration). Gene expression analysis revealed that B8 downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1ß, and nuclear factor-κB (NF-κB) and concurrently upregulated IL-10 expression in contrast to the MTX group. Further, B8 significantly improved the luminal microflora profile by augmenting the growth of Lactobacillus spp. and reducing the number of pathogenic bacteria (E. coli). Additionally, the enzyme-linked immunoassay showed that B8 decreased the levels of pro-inflammatory cytokines. Our findings suggest that B8 had mucoprotective effects against MTX-induced IM and could be used as an adjunct in chemotherapy to deter this side effect.
Assuntos
Benzimidazóis , Metotrexato , Mucosite , Estresse Oxidativo , Animais , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Mucosite/metabolismo , Mucosite/patologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Metotrexato/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/induzido quimicamente , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Biomarcadores/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Antimetabólitos Antineoplásicos/toxicidadeRESUMO
An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.
Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias da Próstata , Masculino , Adulto , Humanos , Diabetes Mellitus Tipo 2/genética , Puberdade/fisiologia , Maturidade Sexual/fisiologia , Obesidade/genéticaRESUMO
The circadian rhythm affects multiple physiological processes, and disruption of the circadian system can be involved in a range of disease-related pathways. The genetic underpinnings of the circadian rhythm have been well-studied in model organisms. Significant progress has been made in understanding how clock genes affect the physiological functions of the nervous system. In addition, circadian timing is becoming a key factor in improving drug efficacy and reducing drug toxicity. The circadian biology of the target cell determines how the organ responds to the drug at a specific time of day, thus regulating pharmacodynamics. The current review brings together recent advances that have begun to unravel the molecular mechanisms of how the circadian clock affects neurophysiological and behavioral processes associated with human brain diseases. We start with a brief description of how the ubiquitous circadian rhythms are regulated at the genetic, cellular, and neural circuit levels, based on knowledge derived from extensive research on model organisms. We then summarize the latest findings from genetic studies of human brain disorders, focusing on the role of human clock gene variants in these diseases. Lastly, we discuss the impact of common dietary factors and medications on human circadian rhythms and advocate for a broader application of the concept of chronomedicine.
Assuntos
Relógios Circadianos , Neurociências , Humanos , Neurofisiologia , Ritmo Circadiano/genética , Relógios Circadianos/genéticaRESUMO
Introduction: Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear. Methods: In this study, the sexual behavior of female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) was examined. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice) to examine the effect on sexual responsiveness. Results: MC4R knockout mice were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. These changes were independent of body weight. Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. Discussion: These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.
Assuntos
Lordose , Receptor Tipo 4 de Melanocortina , Masculino , Camundongos , Animais , Feminino , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Lordose/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Neurônios/metabolismo , Camundongos Knockout , Melanocortinas/metabolismo , Proteínas Repressoras , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
Thermoregulation is the physiological process by which an animal regulates body temperature in response to its environment. It is known that galanin, a neuropeptide widely distributed throughout the central nervous system and secreted by the gut, plays a role in thermoregulatory behaviors and metabolism. We tested the ability of the novel neuropeptide spexin, which shares sequence homology to galanin, to regulate these functions in female mice. Supraphysiological levels of spexin in C57BL/6 mice did not lead to weight loss after 50â¯days of treatment. Behavioral analysis of long-term spexin treatment showed it decreased anxiety and increased thermoregulatory nest building, which was not observed when mice were housed at thermoneutral temperatures. Treatment also disrupted the thermogenic profile of brown and white adipose tissue, decreasing mRNA expression of Ucp1 in BAT and immunodetection of ß3-adrenergic receptors in gWAT. Our results reveal novel functions for spexin as a modulator of thermoregulatory behaviors and adipose tissue metabolism.
Assuntos
Tecido Adiposo Marrom , Galanina , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Regulação da Temperatura Corporal , Feminino , Galanina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin-resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin-responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player.
RESUMO
The hypothalamic-pituitary-gonadal axis is controlled by gonadotropin-releasing hormone (GnRH) released by the hypothalamus. Disruption of this system leads to impaired reproductive maturation and function, a condition known as hypogonadotropic hypogonadism (HH). Most studies to date have focused on genetic causes of HH that impact neuronal development and function. However, variants may also impact the functioning of non-neuronal cells known as glia. Glial cells make up 50% of brain cells of humans, primates, and rodents. They include radial glial cells, microglia, astrocytes, tanycytes, oligodendrocytes, and oligodendrocyte precursor cells. Many of these cells influence the hypothalamic neuroendocrine system controlling fertility. Indeed, glia regulate GnRH neuronal activity and secretion, acting both at their cell bodies and their nerve endings. Recent work has also made clear that these interactions are an essential aspect of how the HPG axis integrates endocrine, metabolic, and environmental signals to control fertility. Recognition of the clinical importance of interactions between glia and the GnRH network may pave the way for the development of new treatment strategies for dysfunctions of puberty and adult fertility.
Assuntos
Células Endócrinas/fisiologia , Hipogonadismo/etiologia , Animais , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Neurônios/fisiologia , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/fisiologia , Reprodução/fisiologiaRESUMO
For over 100 years, essential hypertension has been researched from different perspectives ranging from genetics, physiology, and immunology to more recent ones encompassing microbiology (microbiota) as a previously underappreciated field of study contributing to the cause of hypertension. Each field of study in isolation has uniquely contributed to a variety of underlying mechanisms of blood pressure regulation. Even so, clinical management of essential hypertension has remained somewhat static. We, therefore, asked if there are any converging lines of evidence from these individual fields that could be amenable for a better clinical prognosis. Accordingly, here we present converging evidence which support the view that metabolic dysfunction underlies essential hypertension.
Assuntos
Pressão Sanguínea/fisiologia , Gerenciamento Clínico , Hipertensão Essencial , Metabolismo/fisiologia , Hipertensão Essencial/imunologia , Hipertensão Essencial/metabolismo , Hipertensão Essencial/microbiologia , Hipertensão Essencial/fisiopatologia , Humanos , MicrobiotaRESUMO
Recent work shows that gut microbial dysbiosis contributes to the risk of obesity in children whose mothers consume a high-fat diet (HFD) during both gestation and lactation or during gestation alone. Obesity predisposes children to developing precocious puberty. However, to date, no study has examined how maternal HFD (MHFD) during lactation regulates the gut microbiota (GM), pubertal timing, and fertility of offspring. Here, we found that MHFD during lactation markedly altered the GM of offspring. The pups developed juvenile obesity, early puberty, irregular estrous cycles, and signs of disrupted glucose metabolism. Remarkably, permitting coprophagia between MHFD and maternal normal chow offspring successfully reversed the GM changes as well as early puberty and insulin insensitivity. Our data suggest that microbial reconstitution may prevent or treat early puberty associated with insulin resistance.
Assuntos
Microbioma Gastrointestinal , Lactação , Exposição Materna , Obesidade Infantil/microbiologia , Puberdade Precoce/microbiologia , Animais , Dieta Hiperlipídica , Feminino , Resistência à Insulina , Camundongos Endogâmicos C57BL , Obesidade Infantil/complicaçõesRESUMO
Insulin resistance and obesity are associated with reduced gonadotropin-releasing hormone (GnRH) release and infertility. Mice that lack insulin receptors (IRs) throughout development in both neuronal and non-neuronal brain cells are known to exhibit subfertility due to hypogonadotropic hypogonadism. However, attempts to recapitulate this phenotype by targeting specific neurons have failed. To determine whether astrocytic insulin sensing plays a role in the regulation of fertility, we generated mice lacking IRs in astrocytes (astrocyte-specific insulin receptor deletion [IRKOGFAP] mice). IRKOGFAP males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. In adulthood, IRKOGFAP female mice also exhibited longer, irregular estrus cycles, decreased pregnancy rates, and reduced litter sizes. IRKOGFAP mice show normal sexual behavior but hypothalamic-pituitary-gonadotropin (HPG) axis dysregulation, likely explaining their low fecundity. Histological examination of testes and ovaries showed impaired spermatogenesis and ovarian follicle maturation. Finally, reduced prostaglandin E synthase 2 (PGES2) levels were found in astrocytes isolated from these mice, suggesting a mechanism for low GnRH/luteinizing hormone (LH) secretion. These findings demonstrate that insulin sensing by astrocytes is indispensable for the function of the reproductive axis. Additional work is needed to elucidate the role of astrocytes in the maturation of hypothalamic reproductive circuits.
Assuntos
Astrócitos/metabolismo , Receptor de Insulina/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Prostaglandina-E Sintases/metabolismo , Puberdade Tardia/metabolismoRESUMO
The melanocortin pathway has been implicated in both metabolism and sexual function. When the melanocortin 4 receptor (MC4R) is knocked out globally, male mice display obesity, low sexual desire, and copulatory difficulties; however, it is unclear whether these phenotypes are interdependent. To elucidate the neuronal circuitry involved in sexual dysfunction in MC4R knockouts, we re-expressed the MC4R in these mice exclusively on Sim1 neurons (tbMC4RSim1 mice) or on a subset of Sim1 neurons, namely oxytocin neurons (tbMC4Roxt mice). The groups were matched at young ages to control for the effects of obesity. Interestingly, young MC4R null mice had no deficits in sexual motivation or erectile function. However, MC4R null mice were found to have an increased latency to reach ejaculation compared to control mice, which was restored in both tbMC4RSim1 and tbMC4Roxt mice. These results indicate that melanocortin signaling via the MC4R on oxytocin neurons is important for normal ejaculation independent of the male's metabolic health.
Assuntos
Neurônios/metabolismo , Ocitocina/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Comportamento Sexual Animal , Animais , Feminino , Hormônios Esteroides Gonadais/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND: CEACAM1 regulates insulin sensitivity by promoting insulin clearance. Accordingly, global C57BL/6J.Cc1-/- null mice display hyperinsulinemia due to impaired insulin clearance at 2â¯months of age, followed by insulin resistance, steatohepatitis, visceral obesity and leptin resistance at 6â¯months. The study aimed at investigating the primary role of hepatic CEACAM1 in insulin and lipid homeostasis independently of its metabolic effect in extra-hepatic tissues. METHODS: Liver-specific C57BL/6J.AlbCre+Cc1fl/fl mice were generated and their metabolic phenotype was characterized by comparison to that of their littermate controls at 2-9â¯months of age, using hyperinsulinemic-euglycemic clamp analysis and indirect calorimetry. The effect of hyperphagia on insulin resistance was assessed by pair-feeding experiments. RESULTS: Liver-specific AlbCre+Cc1fl/fl mutants exhibited impaired insulin clearance and hyperinsulinemia at 2â¯months, followed by hepatic insulin resistance (assessed by hyperinsulinemic-euglycemic clamp analysis) and steatohepatitis at ~ 7â¯months of age, at which point visceral obesity and hyperphagia developed, in parallel to hyperleptinemia and blunted hypothalamic STAT3 phosphorylation in response to an intraperitoneal injection of leptin. Hyperinsulinemia caused hypothalamic insulin resistance, followed by increased fatty acid synthase activity, which together with defective hypothalamic leptin signaling contributed to hyperphagia and reduced physical activity. Pair-feeding experiment showed that hyperphagia caused systemic insulin resistance, including blunted insulin signaling in white adipose tissue and lipolysis, at 8-9â¯months of age. CONCLUSION: AlbCre+Cc1fl/fl mutants provide an in vivo demonstration of the key role of impaired hepatic insulin clearance and hyperinsulinemia in the pathogenesis of secondary hepatic insulin resistance independently of lipolysis. They also reveal an important role for the liver-hypothalamic axis in the regulation of energy balance and subsequently, systemic insulin sensitivity.
Assuntos
Antígeno Carcinoembrionário/genética , Hiperinsulinismo/complicações , Resistência à Insulina , Fígado/metabolismo , Animais , Técnica Clamp de Glucose , Hiperfagia/complicações , Hipotálamo/metabolismo , Lipólise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
A minimum amount of energy is required for basic physiological processes, such as protein biosynthesis, thermoregulation, locomotion, cardiovascular function, and digestion. However, for reproductive function and survival of the species, extra energy stores are necessary. Production of sex hormones and gametes, pubertal development, pregnancy, lactation, and parental care all require energy reserves. Thus the physiological systems that control energy homeostasis and reproductive function coevolved in mammals to support both individual health and species subsistence. In this review, we aim to gather scientific knowledge produced by laboratories around the world on the role of the brain in integrating metabolism and reproduction. We describe essential neuronal networks, highlighting key nodes and potential downstream targets. Novel animal models and genetic tools have produced substantial advances, but critical gaps remain. In times of soaring worldwide obesity and metabolic dysfunction, understanding the mechanisms by which metabolic stress alters reproductive physiology has become crucial for human health.
Assuntos
Encéfalo/fisiologia , Doenças Metabólicas/fisiopatologia , Reprodução/fisiologia , Animais , Homeostase/fisiologia , HumanosRESUMO
INTRODUCTION: The methylation level of promoters is one of the most studied and well-known epigenetic mechanisms that programs the amount of gene expression. Over expression of steroidogenesis genes via epigenetic control can result in hypetandrogenism, which is the main endocrine aspect of polycystic ovarian syndrome (PCOS). AIMS: In the present study we aimed to determine and compare the promoter methylation levels of three steroidogenic genes, CYP17, GATA6 and StAR, in theca cells of prenatally androgenized (PNA) rats to those of controls. MATERIALS AND METHODS: Pregnant Wistar rats in the PNA group received 5â¯mg free testosterone, dissolved in 500â¯ml solvent, subcutaneously injected on day 20 of pregnancy, while controls were injected with 500â¯ml of solvent only. Theca cell samples, taken from the ovaries of eight to ten female offspring of both the PNA and control groups, were measured for promoter methylation levels of the aforementioned genes, using the bisulfite sequence PCR (BSP) method. KEY FINDINGS: Although the promoters of all three genes were slightly hypomethylated in the PNA group, the differences observed were not significant compared to the control group. The methylation of -520 and -822 positions, in the GATA6 and the StAR promoter respectively, were significantly decreased in the PNA group. SIGNIFICANCES: The results of this study suggest that alterations in the steroidogenesis pathway after exposure to excess androgen may be a result of changes in the pattern of the methylation of the relevant genes.
Assuntos
Ilhas de CpG , Metilação de DNA , Fator de Transcrição GATA6/genética , Fosfoproteínas/genética , Regiões Promotoras Genéticas , Esteroide 17-alfa-Hidroxilase/genética , Animais , Epigênese Genética , Feminino , Fator de Transcrição GATA6/metabolismo , Expressão Gênica , Masculino , Exposição Materna , Ovário/metabolismo , Fosfoproteínas/metabolismo , Síndrome do Ovário Policístico/metabolismo , Gravidez , Ratos , Ratos Wistar , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/metabolismo , Células Tecais/metabolismo , VirilismoRESUMO
BACKGROUND: Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. RESULTS: The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). CONCLUSIONS: We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in metabolite production of short chain fatty acids. These results suggest that early-life exposure to hyperandrogenemia in daughters of women with PCOS may lead to long-term alterations in gut microbiota and cardiometabolic function.
Assuntos
Androgênios/efeitos adversos , Disbiose/microbiologia , Hipertensão/etiologia , Exposição Materna/efeitos adversos , Síndrome do Ovário Policístico/complicações , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Testosterona/análogos & derivados , Adipocinas/metabolismo , Tecido Adiposo Branco/metabolismo , Adulto , Androgênios/administração & dosagem , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Pressão Sanguínea , Disbiose/etiologia , Disbiose/metabolismo , Disbiose/fisiopatologia , Ácidos Graxos Voláteis/metabolismo , Feminino , Microbioma Gastrointestinal , Frequência Cardíaca , Humanos , Hipertensão/metabolismo , Hipertensão/microbiologia , Hipertensão/fisiopatologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Testosterona/administração & dosagem , Testosterona/efeitos adversosRESUMO
Sexual dysfunction is a poorly understood condition that affects up to one-third of men around the world. Existing treatments that target the periphery do not work for all men. Previous studies have shown that central melanocortins, which are released by pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus, can lead to male erection and increased libido. Several studies specifically implicate the melanocortin 4 receptor (MC4R) in the central control of sexual function, but the specific neural circuitry involved is unknown. We hypothesized that single-minded homolog 1 (Sim1) neurons play an important role in the melanocortin-mediated regulation of male sexual behavior. To test this hypothesis, we examined the sexual behavior of mice expressing MC4R only on Sim1-positive neurons (tbMC4Rsim1 mice) in comparison with tbMC4R null mice and wild-type controls. In tbMC4Rsim1 mice, MC4R reexpression was found in the medial amygdala and paraventricular nucleus of the hypothalamus. These mice were paired with sexually experienced females, and their sexual function and behavior was scored based on mounting, intromission, and ejaculation. tbMC4R null mice showed a longer latency to mount, a reduced intromission efficiency, and an inability to reach ejaculation. Expression of MC4R only on Sim1 neurons reversed the sexual deficits seen in tbMC4R null mice. This study implicates melanocortin signaling via the MC4R on Sim1 neurons in the central control of male sexual behavior.
Assuntos
Tonsila do Cerebelo/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Infertilidade Masculina/metabolismo , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Proteínas Repressoras/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/patologia , Copulação/efeitos dos fármacos , Cruzamentos Genéticos , Fármacos para a Fertilidade Masculina/administração & dosagem , Fármacos para a Fertilidade Masculina/uso terapêutico , Heterozigoto , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/patologia , Injeções Intraventriculares , Masculino , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Especificidade de Órgãos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/patologia , Distribuição Aleatória , Receptor Tipo 4 de Melanocortina/genética , Comportamento Sexual Animal/efeitos dos fármacos , alfa-MSH/administração & dosagem , alfa-MSH/uso terapêuticoRESUMO
The role of PI3K in leptin physiology has been difficult to determine due to its actions downstream of several metabolic cues, including insulin. Here, we used a series of mouse models to dissociate the roles of specific PI3K catalytic subunits and of insulin receptor (InsR) downstream of leptin signaling. We show that disruption of p110α and p110ß subunits in leptin receptor cells (LRΔα+ß) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LRΔα+ß mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110α in LRΔα) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LRΔα mice have normal locomotor activity and thermogenesis. Blunted PI3K in leptin receptor (LR) cells enhanced leptin sensitivity in metabolic regulation due to increased basal hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN levels. However, these mice are unresponsive to leptin's effects on growth and puberty. We further assessed if these phenotypes were associated with disruption of insulin signaling. LRΔInsR mice have no metabolic or growth deficit and show only mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in energy expenditure, growth, and reproduction. These actions are independent from insulin signaling.