Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

Puberty is driven by sophisticated neuroendocrine networks that timely activate the brain centers governing the reproductive axis. The timing of puberty is genetically determined; yet, puberty is also sensitive to numerous internal and external cues, among which metabolic/nutritional signals are especially prominent. Compelling epidemiological evidence suggests that alterations of the age of puberty are becoming more frequent; the underlying mechanisms remain largely unknown, but the escalating prevalence of obesity and other metabolic/feeding disorders is possibly a major contributing factor. This phenomenon may have clinical implications, since alterations in pubertal timing have been associated to adverse health outcomes, including higher risk of earlier all-cause mortality. This urges for a better understanding of the neurohormonal basis of normal puberty and its deviations. Compelling evidence has recently documented the master role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine pathways controlling puberty. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. Key cellular metabolic sensors, as the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and the fuel-sensing deacetylase, SIRT1, have been recently shown to participate also in the metabolic modulation of puberty. Recently, we have documented that AMPK and SIRT1 operate as major molecular effectors for the metabolic control of Kiss1 neurons and, thereby, puberty onset. Alterations of these molecular pathways may contribute to the perturbation of pubertal timing linked to conditions of metabolic stress in humans, such as subnutrition or obesity and might become druggable targets for better management of pubertal disorders.

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Overnutrition, mTOR signaling, and cardiovascular diseases

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00262.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. R1198-R1206 ◽

Cited By ~ 59

Author(s):

Guanghong Jia ◽

Annayya R. Aroor ◽

Luis A. Martinez-Lemus ◽

James R. Sowers

Keyword(s):

Kidney Disease ◽

Nutrient Intake ◽

Mammalian Target Of Rapamycin ◽

Metabolic Stress ◽

The United States ◽

Mtor Signaling ◽

Medical Disorders ◽

Prevalence Of Obesity

The prevalence of obesity and associated medical disorders has increased dramatically in the United States and throughout much of the world in the past decade. Obesity, induced by excess intake of carbohydrates and fats, is a major cause of Type 2 diabetes, hypertension, and the cardiorenal metabolic syndrome. There is emerging evidence that excessive nutrient intake promotes signaling through the mammalian target of rapamycin (mTOR), which, in turn, may lead to alterations of cellular metabolic signaling leading to insulin resistance and obesity-related diseases, such as diabetes, cardiovascular and kidney disease, as well as cancer. While the pivotal role of mTOR signaling in regulating metabolic stress, autophagy, and adaptive immune responses has received increasing attention, there remain many gaps in our knowledge regarding this important nutrient sensor. For example, the precise cellular signaling mechanisms linking excessive nutrient intake and enhanced mTOR signaling with increased cardiovascular and kidney disease, as well as cancer, are not well understood. In this review, we focus on the effects that the interaction between excess intake of nutrients and enhanced mTOR signaling have on the promotion of obesity-associated diseases and potential therapeutic strategies involving targeting mTOR signaling.

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The signaling underlying FITnessThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-035 ◽

2009 ◽

Vol 34 (3) ◽

pp. 411-419 ◽

Cited By ~ 18

Author(s):

Keith Baar

Keyword(s):

Muscle Mass ◽

Peer Review Process ◽

Mammalian Target Of Rapamycin ◽

Metabolic Stress ◽

Force Production ◽

Calcium Flux ◽

Concurrent Training ◽

Endurance Capacity ◽

Amp Activated Protein Kinase ◽

Physical And Chemical

Exercise results in highly specific physiological adaptations. Resistance exercise increases muscle mass and force production, while endurance exercise increases aerobic capacity. As the physical and chemical signals underlying this specificity become better understood, scientists are beginning to identify the key molecular effectors of exercise specificity. This review focuses on how variations in load, metabolic stress, and calcium flux are transduced to increases in muscle mass and endurance capacity. Specific attention is paid to the mammalian target of rapamycin, AMP-activated protein kinase, and the calcium-calmodulin-activated protein kinases, and the way these proteins interact during concurrent training.

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Antifatigue Effects of Antrodia cinnamomea Cultured Mycelium via Modulation of Oxidative Stress Signaling in a Mouse Model

BioMed Research International ◽

10.1155/2017/9374026 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Yange Liu ◽

Lanzhou Li ◽

Shengshu An ◽

Yuanzhu Zhang ◽

Shiwei Feng ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Protein Kinase ◽

Biological Effects ◽

Mammalian Target Of Rapamycin ◽

Stress Signaling ◽

Antrodia Cinnamomea ◽

Underlying Mechanisms ◽

Biochemical Indices ◽

Amp Activated Protein Kinase

Antrodia cinnamomea, a folk medicinal mushroom, has numerous biological effects. In this study, we aim to assess whether the antifatigue effects of A. cinnamomea mycelia (AC) and its underlying mechanisms are related to oxidative stress signaling using behavioral mouse models and biochemical indices detection. Mice were orally treated with AC at doses of 0.1, 0.3, and 0.9 g/kg for three weeks. AC had no effect on the spontaneous activities of mice indicating its safety on central nervous system. Furthermore, results obtained from weight-loaded forced swimming test, rotary rod test, and exhausted running test confirmed that AC significantly enhanced exercise tolerance of mice. Biochemical indices levels showed that these effects were closely correlated with inhibiting the depletion of glycogen and adenosine triphosphate stores, regulating oxidative stress-related parameters (superoxide dismutase, glutathione peroxidase, reactive oxygen species, and malondialdehyde) in serum, skeletal muscle, and liver of mice. Moreover, the effects of AC may be related with its regulation on the activations of AMP-activated protein kinase, protein kinase B, and mammalian target of rapamycin in liver and skeletal muscle of mice. Altogether, our data suggest that the antifatigue properties of AC may be one such modulation mechanism via oxidative stress-related signaling in mice.

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Physiological Roles of Gonadotropin-Inhibitory Hormone Signaling in the Control of Mammalian Reproductive Axis: Studies in the NPFF1 Receptor Null Mouse

Endocrinology ◽

10.1210/en.2014-1030 ◽

2014 ◽

Vol 155 (8) ◽

pp. 2953-2965 ◽

Cited By ~ 57

Author(s):

Silvia León ◽

David García-Galiano ◽

Francisco Ruiz-Pino ◽

Alexia Barroso ◽

María Manfredi-Lozano ◽

...

Keyword(s):

Energy Homeostasis ◽

Pubertal Timing ◽

Metabolic Stress ◽

Gonadal Hormone ◽

Null Mouse ◽

Male Mice ◽

Reproductive Axis ◽

Hypothalamic Arcuate Nucleus ◽

Gonadotropin Inhibitory Hormone ◽

The Impact

RF-amide-related peptide-3 (RFRP-3), the mammalian ortholog of the avian gonadotropin-inhibiting hormone (GnIH), operates via the NPFF1 receptor (NPFF1R) to repress the reproductive axis, therefore acting as counterpart of the excitatory RF-amide peptide, kisspeptin (ligand of Gpr54). In addition, RFRP-3 modulates feeding and might contribute to the integrative control of energy homeostasis and reproduction. Yet, the experimental evidence supporting these putative functions is mostly indirect, and the physiological roles of RFRP-3 remain debatable and obscured by the lack of proper analytical tools and models. To circumvent these limitations, we characterize herein the first mouse line with constitutive inactivation of NPFF1R. Ablation of NPFF1R did not compromise fertility; rather, litters from NPFF1R null mice were larger than those from wild-type animals. Pubertal timing was not altered in NPFF1R deficient mice; yet, pre-pubertal knockout (KO) males displayed elevated LH levels, which normalized after puberty. Adult NPFF1R null male mice showed increased Kiss1 expression in the hypothalamic arcuate nucleus, higher serum FSH levels, and enhanced LH responses to GnRH. However, genetic elimination of NPFF1R was unable to reverse the state of hypogonadism caused by the lack of kisspeptin signaling, as revealed by double NPFF1R/Gpr54 KO mice. NPFF1R null mice displayed altered feedback responses to gonadal hormone withdrawal. In addition, metabolic challenges causing gonadotropin suppression, such as short-term fasting and high-fat diet, were less effective in dampening LH secretion in NPFF1R-deficient male mice, suggesting that absence of this inhibitory pathway partially prevented gonadotropin suppression by metabolic stress. Our data are the first to document the impact of elimination of GnIH signaling on reproductive parameters and their modulation by metabolic challenges. Whereas, in keeping with its inhibitory role, the NPFF1R pathway seems dispensable for preserved puberty and fertility, our results surface different alterations due to the lack of GnIH signaling that prominently include changes in the sensitivity to fasting- and obesity-associated hypogonadotropism.

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Neuropeptide Control of Puberty: Beyond Kisspeptins

Seminars in Reproductive Medicine ◽

10.1055/s-0039-3400967 ◽

2019 ◽

Vol 37 (04) ◽

pp. 155-165 ◽

Cited By ~ 1

Author(s):

Alexia Barroso ◽

Juan Roa ◽

Manuel Tena-Sempere

Keyword(s):

Metabolic Regulation ◽

Arcuate Nucleus ◽

Pubertal Timing ◽

Metabolic Stress ◽

Reproductive Capacity ◽

Environmental Cues ◽

Genetic Determination ◽

Regulatory Circuits ◽

Amp Activated Protein Kinase ◽

The Brain

AbstractPuberty is a fundamental developmental event in the lifespan of any individual, when sexual and somatic maturation is completed, and reproductive capacity is achieved. While the tempo of puberty is under strong genetic determination, it is also modulated by a wide array of internal and environmental cues, including, prominently, nutritional and metabolic signals. In the last decade, our understanding of the neurohormonal basis of normal puberty and its perturbations has enlarged considerably. This is illustrated by the elucidation of the essential roles of kisspeptins, encoded by the Kiss1 gene, in the hypothalamic circuits controlling puberty. Moreover, other neuropeptide pathways, convergent with kisspeptin signaling, have been pointed out as important coregulators of pubertal timing. These include the cotransmitters of Kiss1 neurons in the arcuate nucleus (ARC), neurokinin B, and dynorphin, as well as melanocortins, produced by ARC neurons expressing proopiomelanocortin, which are endowed with key roles also in the control of metabolic homeostasis. This neuropeptide setup seemingly participates, in a coordinated manner, in transmitting the regulatory actions of metabolic cues on pubertal maturation. In this function, cellular metabolic sensors, such as the AMP-activated protein kinase, and the fuel-sensing deacetylase, SIRT1, have also been shown recently to contribute to the metabolic regulation of puberty. Altogether, elucidation of the physiological roles of these signals and regulatory circuits will help uncover the intimacies of the brain control of puberty, and its alterations in conditions of metabolic stress, ranging from subnutrition to obesity.

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Metformin – its potential anti-cancer and anti-aging effects

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0010.3801 ◽

2017 ◽

Vol 71 (1) ◽

pp. 0-0 ◽

Cited By ~ 17

Author(s):

Monika Podhorecka ◽

Blanca Ibanez ◽

Anna Dmoszyńska

Keyword(s):

Metabolic Stress ◽

Glucose Deprivation ◽

Adenosine Monophosphate ◽

Aging Effects ◽

Beneficial Effects ◽

Anti Cancer ◽

Aging Properties ◽

Treatment Of Diabetes ◽

Underlying Mechanisms ◽

Amp Activated Protein Kinase

The generally accepted mechanism of metformin’s effect is stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is directly activated by an increase in AMP:ATP ratio in metabolic stress conditions including hypoxia and glucose deprivation. Lately, many novel pathways, besides AMPK induction, have been revealed, which can explain some of metformin’s beneficial effects. It may help to identify new targets for treatment of diabetes and metabolic syndrome. Moreover, metformin is now attracting the attention of researchers in fields other than diabetes, as it has been shown to have anti-cancer, immunoregulatory and anti-aging effects. The aim of this review is to describe the potential anti-cancer and anti-aging properties of metformin and discuss the possible underlying mechanisms.

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Minocycline inhibits mTOR signaling activation and alleviates behavioral deficits in the Wistar rats with acute ischemia stroke

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319999200831153748 ◽

2020 ◽

Vol 19 ◽

Author(s):

Shengyuan Wang ◽

Chuanling Wang ◽

Lihua Wang ◽

Zhiyou Cai

Keyword(s):

Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Acute Ischemia ◽

Intragastric Administration ◽

Underlying Mechanisms ◽

Signaling Activation ◽

The Brain ◽

Minocycline Therapy

Background: Mammalian target of rapamycin (mTOR) has been evidenced as a multimodal therapy in the path-ophysiological process of acute ischemic stroke (AIS). However, the pathway that minocycline targets mTOR signaling is not fully defined in the AIS pathogenesis. This study is to aim at the effects of minocycline on the mTOR signaling in the AIS process and further discover the underlying mechanisms of minocycline involved in the following change of mTOR signaling-autophagy. Methods: Cerebral ischemia/reperfusion (CIR) rat animal models were established with the transient suture occlusion into middle cerebral artery. Minocycline (50mg/kg) was given by intragastric administration. The Morris water maze was used to test the cognitive function of animals. Immunohistochemistry and immunofluorescence were introduced for testing the lev-els of synaptophysin and PSD-95. Western blot was conducted for investigating the levels of mTOR, p-mTOR (Ser2448), p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366), p-eIF4B (Ser406), LC3, p62, synaptophysin and PSD-95. Results: Minocycline prevents cognitive decline of the MCAO stroke rats. Minocycline limits the expression of p-mTOR (Ser2448) and the downstream targets of mTOR [p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366) and p-eIF4B (Ser406)] (P<0.01), while minocycline has no influence on mTOR. LC3-II abundance and the LC3-II/I ratio were upregu-lated in the hippocampus of the MCAO stroke rats by the minocycline therapy (P<0.01). p62 was downregulated in the hippocampus from the MCAO stroke rats administrated with minocycline therapy(P<0.01). The levels of SYP and PSD-95 were up-regulated in the brain of the MCAO stroke rats administrated with minocycline therapy. Conclusion: Minocycline prevents cognitive deficits via inhibiting mTOR signaling and enhancing autophagy process, and promoting the expression of pre-and postsynaptic proteins (synaptophysin and PSD-95) in the brain of the MCAO stroke rats. The potential neuroprotective role of minocycline in the process of cerebral ischemia may be related to mitigating is-chemia-induced synapse injury via inhibiting activation of mTOR signaling.

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The Demethoxy Derivatives of Curcumin Exhibit Greater Differentiation Suppression in 3T3-L1 Adipocytes Than Curcumin: A Mechanistic Study of Adipogenesis and Molecular Docking

Biomolecules ◽

10.3390/biom11071025 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1025

Author(s):

Ahmed Alalaiwe ◽

Jia-You Fang ◽

Hsien-Ju Lee ◽

Chun-Hui Chiu ◽

Ching-Yun Hsu

Keyword(s):

Molecular Docking ◽

Fatty Acid Synthase ◽

Structural Similarity ◽

Mechanistic Study ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Enhancer Binding Protein ◽

Underlying Mechanisms ◽

Amp Activated Protein Kinase

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

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Identification and characterization of a novel sucrose-non-fermenting protein kinase/AMP-activated protein kinase-related protein kinase, SNARK

Biochemical Journal ◽

10.1042/bj3550297 ◽

2001 ◽

Vol 355 (2) ◽

pp. 297-305 ◽

Cited By ~ 25

Author(s):

Diana L. LEFEBVRE ◽

Yahong BAI ◽

Nazanin SHAHMOLKY ◽

Monika SHARMA ◽

Raymond POON ◽

...

Keyword(s):

Protein Kinase ◽

Cellular Response ◽

Catalytic Domain ◽

Metabolic Stress ◽

Glucose Deprivation ◽

Protein Band ◽

Northern Blotting ◽

Significant Similarity ◽

Amp Activated Protein Kinase

Subtraction hybridization after the exposure of keratinocytes to ultraviolet radiation identified a differentially expressed cDNA that encodes a protein of 630 amino acid residues possessing significant similarity to the catalytic domain of the sucrose-non-fermenting protein kinase (SNF1)/AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. Northern blotting and reverse-transcriptase-mediated PCR demonstrated that mRNA transcripts for the SNF1/AMPK-related kinase (SNARK) were widely expressed in rodent tissues. The SNARK gene was localized to human chromosome 1q32 by fluorescent in situ hybridization. SNARK was translated in vitro to yield a single protein band of approx. 76kDa; Western analysis of transfected baby hamster kidney (BHK) cells detected two SNARK-immunoreactive bands of approx. 76-80kDa. SNARK was capable of autophosphorylation in vitro; immunoprecipitated SNARK exhibited phosphotransferase activity with the synthetic peptide substrate HMRSAMSGLHLVKRR (SAMS) as a kinase substrate. SNARK activity was significantly increased by AMP and 5-amino-4-imidazolecarboxamide riboside (AICAriboside) in rat keratinocyte cells, implying that SNARK might be activated by an AMPK kinase-dependent pathway. Furthermore, glucose deprivation increased SNARK activity 3-fold in BHK fibroblasts. These findings identify SNARK as a glucose- and AICAriboside-regulated member of the AMPK-related gene family that represents a new candidate mediator of the cellular response to metabolic stress.

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Aucubin Protects against TGFβ1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKα/mTOR Signaling Pathway

Planta Medica ◽

10.1055/s-0043-118663 ◽

2017 ◽

Vol 84 (02) ◽

pp. 91-99 ◽

Cited By ~ 6

Author(s):

Yang Xiao ◽

Wei Chang ◽

Qing-Qing Wu ◽

Xiao-Han Jiang ◽

Ming-Xia Duan ◽

...

Keyword(s):

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Smooth Muscle Actin ◽

Mammalian Target Of Rapamycin ◽

Transforming Growth Factor Β1 ◽

Neonatal Rat ◽

Cell Counting ◽

Compound C ◽

Underlying Mechanisms

AbstractFibrosis is a key feature of various cardiovascular diseases and compromises cardiac systolic and diastolic performance. The lack of effective anti-fibrosis drugs is a major contributor to the increasing prevalence of heart failure. The present study was performed to investigate whether the iridoid aucubin alleviates cardiac fibroblast activation and its underlying mechanisms. Neonatal rat cardiac fibroblasts were incubated with aucubin (1, 10, 20, 50 µM) followed by transforming growth factor β1 (TGFβ1, 10 ng/mL) stimulation for 24 h. Fibrosis proliferation was measured by cell counting kit-8 assay. The differentiation of fibroblasts into myofibroblasts was determined by measuring the expression of α-smooth muscle actin. Then, the expressions levels of cardiac fibrosis-related proteins in myofibroblasts were analyzed by western blot and real-time PCR to confirm the anti-fibrosis effect of aucubin. As a result, aucubin suppressed TGFβ1-induced proliferation in fibroblasts and inhibited the TGFβ1-induced activation of fibroblasts to myofibroblasts. In addition, aucubin further attenuated fibrosis-related protein expression in myofibroblasts. Furthermore, this protective effect was related to increased adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, which was confirmed by an mTOR inhibitor (rapamycin), an AMPK agonist (AICAR) and an AMPKα inhibitor compound C. Collectively, our findings suggest that aucubin protects against TGFβ1-induced fibroblast proliferation, activation and function by regulating the AMPKα/mTOR signal axis.

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