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1.
Int J Mol Sci ; 24(4)2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36835587

RESUMO

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational parent/fetal exchange, and ultimately, fetal development and growth. Not surprisingly, in cases of placental dysfunction-where aspects of placental development or function become compromised-adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.


Assuntos
Hipertensão , Doenças Placentárias , Pré-Eclâmpsia , Recém-Nascido , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/patologia , Placenta/patologia , Resultado da Gravidez , Hipertensão/patologia , Mitocôndrias/patologia , Doenças Placentárias/patologia
2.
Mol Metab ; 65: 101575, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35987498

RESUMO

OBJECTIVE: The epidermal barrier is renewed by the activation, proliferation, and differentiation of keratinocyte stem cells after injury and aging impedes this repair process through undefined mechanisms. We previously identified a gene signature of metabolic dysfunction in aged murine epidermis, but the precise regulators of epidermal repair and age-related growth defects are not well established. Aged mouse models as well as mice with conditional epidermal loss of the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1α) were used to explore the cellular pathways which control skin repair after injury and stress. METHODS: Aged mice or those with epidermal Pgc-1α deletion (epiPgc-1α KO) and young or Pgc1afl/fl controls were subjected to wound injury, UVB exposure or the inflammatory agent TPA. In vivo and ex vivo analyses of wound closure, skin structure, cell growth and stem cell differentiation were used to understand changes in epidermal re-growth and repair resulting from aging or Pgc-1α loss. RESULTS: Aging impairs epidermal re-growth during wound healing and results in lower expression of Pgc-1α. Mice with conditional deletion of epidermal Pgc-1α exhibit greater inflammation- and UVB-induced cell differentiation, reduced proliferation, and slower wound healing. epiPgc-1α KO mice also displayed reduced keratinocyte NAD+ levels, shorter telomeres, and greater poly ADP-ribosylation, resulting in enhanced stress-stimulated p53 and p21 signaling. When NAD+ was reduced by Pgc-1α loss or pharmacologic inhibition of NAD+ synthesis, there was reduced stress-induced proliferation, increased differentiation, and protection against DNA damage via enhanced epidermal shedding. Similarly, aged mice exhibit disrupted epidermal NAD+ homeostasis and enhanced p53 activation, resulting in p21 growth arrest after wounding. NAD+ precursor treatment restores epidermal growth from old skin to that of young. CONCLUSIONS: Our studies identify a novel role for epidermal Pgc-1α in controlling epidermal repair via its regulation of cellular NAD+ and downstream effects on p53-driven growth arrest. We also establish that parallel mechanisms are evident in aged epidermis, showing that NAD+ signaling is an important controller of physiologic skin repair and that dysfunction of this pathway contributes to age-related wound repair defects.


Assuntos
NAD , PPAR gama , Envelhecimento/metabolismo , Animais , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , NAD/metabolismo , PPAR gama/metabolismo , Células-Tronco/metabolismo , Proteína Supressora de Tumor p53
3.
Biochem J ; 477(12): 2347-2361, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32510137

RESUMO

Sodium-glucose cotransporter 2 inhibitors such as canagliflozin lower blood glucose and reduce cardiovascular events in people with type 2 diabetes through mechanisms that are not fully understood. Canagliflozin has been shown to increase the activity of the AMP-activated protein kinase (AMPK), a metabolic energy sensor important for increasing fatty acid oxidation and energy expenditure and suppressing lipogenesis and inflammation, but whether AMPK activation is important for mediating some of the beneficial metabolic effects of canagliflozin has not been determined. We, therefore, evaluated the effects of canagliflozin in female ApoE-/- and ApoE-/-AMPK ß1-/- mice fed a western diet. Canagliflozin increased fatty acid oxidation and energy expenditure and lowered adiposity, blood glucose and the respiratory exchange ratio independently of AMPK ß1. Canagliflozin also suppressed liver lipid synthesis and the expression of ATP-citrate lyase, acetyl-CoA carboxylase and sterol response element-binding protein 1c independently of AMPK ß1. Canagliflozin lowered circulating IL-1ß and studies in bone marrow-derived macrophages indicated that in contrast with the metabolic adaptations, this effect required AMPK ß1. Canagliflozin had no effect on the size of atherosclerotic plaques in either ApoE-/- and ApoE-/-AMPK ß1-/- mice. Future studies investigating whether reductions in liver lipid synthesis and macrophage IL-1ß are important for the cardioprotective effects of canagliflozin warrant further investigation.


Assuntos
Apolipoproteínas E/fisiologia , Canagliflozina/farmacologia , Interleucina-1beta/fisiologia , Lipogênese , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Metabolismo Energético , Feminino , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout para ApoE , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia
4.
J Pharmacol Exp Ther ; 363(3): 367-376, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28928121

RESUMO

Current knowledge regarding acute regulation of adipocyte lipolysis is largely based on receptor-mediated activation or inhibition of pathways that influence intracellular levels of cAMP, thereby affecting protein kinase A (PKA) activity. We recently identified synthetic ligands of α-ß-hydrolase domain containing 5 (ABHD5) that directly activate adipose triglyceride lipase (ATGL) by dissociating ABHD5 from its inhibitory regulator, perilipin-1 (PLIN1). In the current study, we used these novel ligands to determine the direct contribution of ABHD5 to various aspects of lipolysis control in white (3T3-L1) and brown adipocytes. ABHD5 ligands stimulated adipocyte lipolysis without affecting PKA-dependent phosphorylation on consensus sites of PLIN1 or hormone-sensitive lipase (HSL). Cotreatment of adipocytes with synthetic ABHD5 ligands did not alter the potency or maximal lipolysis efficacy of the ß-adrenergic receptor (ADRB) agonist isoproterenol (ISO), indicating that both target a common pool of ABHD5. Reducing ADRB/PKA signaling with insulin or desensitizing ADRB suppressed lipolysis responses to a subsequent challenge with ISO, but not to ABHD5 ligands. Lastly, despite strong treatment differences in PKA-dependent phosphorylation of HSL, we found that ligand-mediated activation of ABHD5 led to complete triglyceride hydrolysis, which predominantly involved ATGL, but also HSL. These results indicate that the overall pattern of lipolysis controlled by ABHD5 ligands is similar to that of isoproterenol, and that ABHD5 plays a central role in the regulation of adipocyte lipolysis. As lipolysis is critical for adaptive thermogenesis and in catabolic tissue remodeling, ABHD5 ligands may provide a means of activating these processes under conditions where receptor signaling is compromised.


Assuntos
1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Piperazinas/farmacologia , Tiazepinas/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Animais , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática , Feminino , Hidrólise , Insulina/farmacologia , Ligantes , Lipólise , Camundongos , Perilipina-1/metabolismo , Fosforilação , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo
5.
Mol Metab ; 5(10): 1048-1056, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27689018

RESUMO

OBJECTIVE: The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. METHODS: Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. RESULTS: Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. CONCLUSION: These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.

6.
Diabetes ; 65(11): 3352-3361, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27554471

RESUMO

Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the ß1 subunit, but whether salsalate requires AMPK-ß1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-ß1-knockout (AMPK-ß1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (∼1 mmol/L). Salsalate treatment increased VO2, lowered fasting glucose, improved glucose tolerance, and led to an ∼55% reduction in liver lipid content. These effects were observed in both WT and AMPK-ß1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton conductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fígado/metabolismo , Mitocôndrias/metabolismo , Salicilatos/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Knockout
7.
Cell Metab ; 24(1): 118-29, 2016 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-27411013

RESUMO

Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK ß subunits in adipocytes (iß1ß2AKO) and found that iß1ß2AKO mice were cold intolerant and resistant to ß-adrenergic activation of BAT and beiging of WAT. BAT from iß1ß2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iß1ß2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/enzimologia , Tecido Adiposo Bege/enzimologia , Tecido Adiposo Marrom/enzimologia , Fígado Gorduroso/enzimologia , Resistência à Insulina , Adipócitos/efeitos dos fármacos , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Ativação Enzimática/efeitos dos fármacos , Fígado Gorduroso/patologia , Deleção de Genes , Homeostase/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Norepinefrina/farmacologia , Termogênese/efeitos dos fármacos
8.
J Appl Physiol (1985) ; 119(11): 1303-12, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26384407

RESUMO

We tested the hypothesis that ingestion of sodium bicarbonate (NaHCO3) prior to an acute session of high-intensity interval training (HIIT) would augment signaling cascades and gene expression linked to mitochondrial biogenesis in human skeletal muscle. On two occasions separated by ∼1 wk, nine men (mean ± SD: age 22 ± 2 yr, weight 78 ± 13 kg, V̇O(2 peak) 48 ± 8 ml·kg(-1)·min(-1)) performed 10 × 60-s cycling efforts at an intensity eliciting ∼90% of maximal heart rate (263 ± 40 W), interspersed with 60 s of recovery. In a double-blind, crossover manner, subjects ingested a total of 0.4 g/kg body weight NaHCO3 before exercise (BICARB) or an equimolar amount of a placebo, sodium chloride (PLAC). Venous blood bicarbonate and pH were elevated at all time points after ingestion (P < 0.05) in BICARB vs. PLAC. During exercise, muscle glycogen utilization (126 ± 47 vs. 53 ± 38 mmol/kg dry weight, P < 0.05) and blood lactate accumulation (12.8 ± 2.6 vs. 10.5 ± 2.8 mmol/liter, P < 0.05) were greater in BICARB vs. PLAC. The acute exercise-induced increase in the phosphorylation of acetyl-CoA carboxylase, a downstream marker of AMP-activated protein kinase activity, and p38 mitogen-activated protein kinase were similar between treatments (P > 0.05). However, the increase in PGC-1α mRNA expression after 3 h of recovery was higher in BICARB vs. PLAC (approximately sevenfold vs. fivefold compared with rest, P < 0.05). We conclude that NaHCO3 before HIIT alters the mRNA expression of this key regulatory protein associated with mitochondrial biogenesis. The elevated PGC-1α mRNA response provides a putative mechanism to explain the enhanced mitochondrial adaptation observed after chronic HIIT supplemented with NaHCO3 in rats.


Assuntos
Exercício Físico/fisiologia , RNA Mensageiro/biossíntese , Bicarbonato de Sódio/farmacologia , Fatores de Transcrição/biossíntese , Adulto , Bicarbonatos/sangue , Estudos Cross-Over , Método Duplo-Cego , Glicogênio/metabolismo , Frequência Cardíaca/fisiologia , Humanos , Masculino , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosforilação , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/genética
9.
Cell Metab ; 21(6): 883-90, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-26039451

RESUMO

The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/metabolismo , Autofagia , Jejum/efeitos adversos , Hipoglicemia/enzimologia , Músculo Esquelético/enzimologia , Doenças Musculares/enzimologia , Proteínas Quinases Ativadas por AMP/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Ativação Enzimática/genética , Hipoglicemia/etiologia , Hipoglicemia/genética , Hipoglicemia/patologia , Camundongos , Camundongos Knockout , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia
10.
Eur J Appl Physiol ; 113(1): 259-66, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22684371

RESUMO

The purpose of the present study was to examine changes in VO(2peak), VO(2) kinetics and steady-state exercise performance following 4 weeks of participation in recreational sport. Subjects (male n = 8, female n = 9) participated in recreational sport (basketball, floor hockey and soccer) four times per week for 4 weeks. Both before and after training, VO(2peak) was measured on a cycle ergometer, VO(2) kinetics was determined as the average of three transitions to 80 W, and heart rate (HR) and respiratory exchange ratio (RER) were measured during 60 min at a work rate corresponding to 50 % of pre-training VO(2peak). HR was also monitored during all training sessions. After training, VO(2peak) was increased in females, but not males, while VO(2) kinetics (τVO(2)) were sped in both males and females. HR during constant load exercise was reduced in both males and females, but exercise RER was only reduced in females. Mean HR during participation in sport was higher in males than females and higher during basketball than both floor hockey and soccer. These results demonstrate that training adaptations traditionally associated with endurance exercise can also be obtained through regular participation in recreational sport.


Assuntos
Desempenho Atlético/fisiologia , Exercício Físico/fisiologia , Consumo de Oxigênio/fisiologia , Esforço Físico/fisiologia , Recreação/fisiologia , Feminino , Humanos , Masculino , Adulto Jovem
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