PURPOSE OF REVIEW: The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS: Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.
- Klíčová slova
- Bone marrow adipose tissue, Bone marrow mesenchymal stem cells, Insulin signaling, Marrow adiposity,
- MeSH
- adipogeneze MeSH
- buněčná diferenciace MeSH
- buňky kostní dřeně metabolismus MeSH
- glukagonu podobný peptid 1 metabolismus MeSH
- glukosa metabolismus MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- inzulin metabolismus MeSH
- inzulinová rezistence MeSH
- kosti a kostní tkáň metabolismus MeSH
- kostní dřeň metabolismus MeSH
- lidé MeSH
- metabolické nemoci kostí metabolismus MeSH
- mezenchymální kmenové buňky metabolismus MeSH
- obezita metabolismus MeSH
- parathormon metabolismus MeSH
- protein 4 vázající insulinu podobné růstové faktory metabolismus MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- receptor inzulinu metabolismus MeSH
- receptor pro konečné produkty pokročilé glykace metabolismus MeSH
- stárnutí buněk * MeSH
- tuková tkáň metabolismus MeSH
- tukové buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- glukagonu podobný peptid 1 MeSH
- glukosa MeSH
- insulinu podobný růstový faktor I MeSH
- inzulin MeSH
- parathormon MeSH
- protein 4 vázající insulinu podobné růstové faktory MeSH
- proteiny insulinového receptorového substrátu MeSH
- receptor inzulinu MeSH
- receptor pro konečné produkty pokročilé glykace MeSH
BACKGROUND/OBJECTIVES: Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm11-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters. SUBJECTS/METHODS: The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm11-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured. RESULTS: At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm11-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm11-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure. CONCLUSIONS: We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.
- MeSH
- glukagon krev MeSH
- glukózový toleranční test MeSH
- hormon uvolňující prolaktin aplikace a dávkování analogy a deriváty farmakologie terapeutické užití MeSH
- hypertenze krev farmakoterapie MeSH
- inzulin krev metabolismus MeSH
- inzulinová rezistence MeSH
- krevní glukóza metabolismus MeSH
- krevní tlak účinky léků MeSH
- lipidy krev MeSH
- metabolický syndrom * krev farmakoterapie metabolismus MeSH
- mozek účinky léků metabolismus MeSH
- obezita * krev farmakoterapie MeSH
- porucha glukózové tolerance * krev farmakoterapie MeSH
- potkani inbrední SHR MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukagon MeSH
- hormon uvolňující prolaktin MeSH
- inzulin MeSH
- krevní glukóza MeSH
- lipidy MeSH
- proteiny insulinového receptorového substrátu MeSH
Autophagy favors both cell survival and cancer suppression, and increasing evidence reveals that microRNAs (MIRs) regulate autophagy. Previously we reported that MIR126 is downregulated in malignant mesothelioma (MM). Therefore, we investigated the role of MIR126 in the regulation of cell metabolism and autophagy in MM models. We report that MIR126 induces autophagic flux in MM cells by downregulating insulin receptor substrate-1 (IRS1) and disrupting the IRS1 signaling pathway. This was specific to MM cells, and was not observed in non-malignant cells of mesothelial origin or in MM cells expressing MIR126-insensitive IRS1 transcript. The MIR126 effect on autophagy in MM cells was recapitulated by IRS1 silencing, and antagonized by IRS1 overexpression or antisense MIR126 treatment. The MIR126-induced loss of IRS1 suppressed glucose uptake, leading to energy deprivation and AMPK-dependent phosphorylation of ULK1. In addition, MIR126 stimulated lipid droplet accumulation in a hypoxia-inducible factor-1α (HIF1α)-dependent manner. MIR126 also reduced pyruvate dehydrogenase kinase (PDK) and acetyl-CoA-citrate lyase (ACL) expression, leading to the accumulation of cytosolic citrate and paradoxical inhibition of pyruvate dehydrogenase (PDH) activity. Simultaneous pharmacological and genetic intervention with PDK and ACL activity phenocopied the effects of MIR126. This suggests that in MM MIR126 initiates a metabolic program leading to high autophagic flux and HIF1α stabilization, incompatible with tumor progression of MM. Consistently, MIR126-expressing MM cells injected into immunocompromised mice failed to progress beyond the initial stage of tumor formation, showing that increased autophagy has a protective role in MM.
- Klíčová slova
- MIR126, autophagy, cell metabolism, malignant mesothelioma, tumor suppression,
- MeSH
- 3' nepřekládaná oblast genetika MeSH
- autofagie genetika MeSH
- buněčné linie MeSH
- down regulace MeSH
- lidé MeSH
- mezoteliom genetika metabolismus patologie MeSH
- mikro RNA genetika MeSH
- myši inbrední BALB C MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádory plic genetika metabolismus patologie MeSH
- proteiny insulinového receptorového substrátu genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sekvence nukleotidů MeSH
- sekvenční homologie nukleových kyselin MeSH
- signální transdukce genetika MeSH
- stanovení celkové genové exprese metody MeSH
- transplantace heterologní MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 3' nepřekládaná oblast MeSH
- IRS1 protein, human MeSH Prohlížeč
- mikro RNA MeSH
- MIRN126 microRNA, human MeSH Prohlížeč
- proteiny insulinového receptorového substrátu MeSH
Strenuous exercise induces delayed-onset muscle damage including oxidative damage of cellular components. Oxidative stress to muscle cells impairs glucose uptake via disturbance of insulin signaling pathway. We investigated glucose uptake and insulin signaling in relation to oxidative protein modification in muscle after acute strenuous exercise. ICR mice were divided into sedentary and exercise groups. Mice in the exercise group performed downhill running exercise at 30 m/min for 30 min. At 24 hr after exercise, metabolic performance and insulin-signaling proteins in muscle tissues were examined. In whole body indirect calorimetry, carbohydrate utilization was decreased in the exercised mice along with reduction of the respiratory exchange ratio compared to the rested control mice. Insulin-stimulated uptake of 2-deoxy-[(3)H]glucose in damaged muscle was decreased after acute exercise. Tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidyl-3-kinase/Akt signaling were impaired by exercise, leading to inhibition of the membrane translocation of glucose transporter 4. We also found that acute exercise caused 4-hydroxy-nonenal modification of IRS-1 along with elevation of oxidative stress in muscle tissue. Impairment of insulin-induced glucose uptake into damaged muscle after strenuous exercise would be related to disturbance of insulin signal transduction by oxidative modification of IRS-1.
- MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- glukosa metabolismus MeSH
- inzulin metabolismus MeSH
- kondiční příprava zvířat * MeSH
- kosterní svaly metabolismus MeSH
- myši inbrední ICR MeSH
- myši MeSH
- oxidace-redukce MeSH
- oxidační stres MeSH
- přenašeč glukosy typ 4 metabolismus MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fosfatidylinositol-3-kinasy MeSH
- glukosa MeSH
- inzulin MeSH
- Irs1 protein, mouse MeSH Prohlížeč
- přenašeč glukosy typ 4 MeSH
- proteiny insulinového receptorového substrátu MeSH
- protoonkogenní proteiny c-akt MeSH
Using PCR and inverse PCR techniques we obtained a 4,498 bp nucleotide sequence FN424076 encompassing the complete coding sequence of the porcine insulin receptor substrate 4 (IRS4) gene and its proximal promoter. The 1,269 amino acid porcine protein deduced from the nucleotide sequence shares 92% identity with the human IRS4 and possesses the same domains and the same number of tyrosine phosphorylation motifs as the human protein. We detected substitution FN424076:g.96C
- MeSH
- celogenomová asociační studie MeSH
- DNA primery genetika MeSH
- fenotyp * MeSH
- jednonukleotidový polymorfismus genetika MeSH
- klonování DNA MeSH
- lineární modely MeSH
- mapování chromozomů MeSH
- molekulární sekvence - údaje MeSH
- polymerázová řetězová reakce MeSH
- prasata genetika MeSH
- proteiny insulinového receptorového substrátu genetika MeSH
- sekvence nukleotidů MeSH
- sekvenční analýza DNA MeSH
- sekvenční homologie MeSH
- tělesné váhy a míry MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA primery MeSH
- proteiny insulinového receptorového substrátu MeSH
