A previous study on neuropeptide FF receptor 2 (NPFFR2)-deficient mice has demonstrated that NPFFR2 is involved in the control of energy balance and thermogenesis. Here, we report on the metabolic impact of NPFFR2 deficiency in male and female mice that were fed either a standard diet (STD) or a high-fat diet (HFD) and each experimental group consisted of ten individuals. Both male and female NPFFR2 knockout (KO) mice exhibited severe glucose intolerance that was exacerbated by a HFD diet. In addition, reduced insulin pathway signaling proteins in NPFFR2 KO mice fed a HFD resulted in the development of hypothalamic insulin resistance. HFD feeding did not cause liver steatosis in NPFFR2 KO mice of either sex, but NPFFR2 KO male mice fed a HFD had lower body weights, white adipose tissues, and liver and lower plasma leptin levels compared with their wild-type (WT) controls. Lower liver weight in NPFFR2 KO male mice compensated for HFD-induced metabolic stress by increased liver PPARα and plasma FGF21 hepatokine, which supported fatty acid β-oxidation in the liver and white adipose tissue. Conversely, NPFFR2 deletion in female mice attenuated the expression of Adra3β and Pparγ, which inhibited lipolysis in adipose tissue.
- MeSH
- bílá tuková tkáň metabolismus MeSH
- dieta s vysokým obsahem tuků MeSH
- glukosa metabolismus MeSH
- inzulinová rezistence * MeSH
- játra metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- obezita metabolismus MeSH
- porucha glukózové tolerance * metabolismus MeSH
- tuková tkáň metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Obesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as "brown" and "brite/beige" adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes. Here we apply methods to greatly expand human adipocyte progenitors from small samples of human subcutaneous adipose tissue and then disrupt the thermogenic suppressor gene NRIP1 by CRISPR. Ribonucleoprotein consisting of Cas9 and sgRNA delivered ex vivo are fully degraded by the human cells following high efficiency NRIP1 depletion without detectable off-target editing. Implantation of such CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreases adiposity and liver triglycerides while enhancing glucose tolerance compared to implantation with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic enhancement of human adipocytes without exposing the recipient to immunogenic Cas9 or delivery vectors.
- MeSH
- bílé tukové buňky metabolismus MeSH
- buněčná diferenciace MeSH
- buněčné kultury metody MeSH
- CRISPR-Cas systémy genetika MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- dospělé kmenové buňky fyziologie MeSH
- editace genu metody MeSH
- guide RNA, Kinetoplastida genetika MeSH
- hnědé tukové buňky metabolismus transplantace MeSH
- lidé MeSH
- metabolismus lipidů genetika MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nuclear receptor interacting protein 1 genetika metabolismus MeSH
- obezita komplikace metabolismus terapie MeSH
- podkožní tuk cytologie MeSH
- porucha glukózové tolerance etiologie metabolismus terapie MeSH
- termogeneze genetika MeSH
- ztučnělá játra etiologie metabolismus prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Complex metabolic conditions such as type 2 diabetes and obesity result from the interaction of numerous genetic and environmental factors. While the family of Nme proteins has been connected so far mostly to development, proliferation, or ciliary functions, several lines of evidence from human and experimental studies point to the potential involvement of one of its members, NME7 (non-metastatic cells 7, nucleoside diphosphate kinase 7) in carbohydrate and lipid metabolism. As a complete lack of Nme7 is semilethal in rats, we compared morphometric, metabolic, and transcriptomic profiles of standard diet-fed heterozygous Nme7+/- on male rats vs. their wild-type Nme7+/+ controls. Nme7+/- animals showed increased body weight, adiposity, higher insulin levels together with decreased glucose tolerance. Moreover, they displayed pancreatic islet fibrosis and kidney tubular damage. Despite no signs of overt liver steatosis or dyslipidemia, we found significant changes in the hepatic transcriptome of Nme7+/- male rats with a concerted increase of expression of lipogenic enzymes including Scd1, Fads1, Dhcr7 and a decrease of Cyp7b1 and Nme7. Network analyses suggested possible links between Nme7 and the activation of Srebf1 and Srebf2 upstream regulators. These results further support the implication of NME7 in the pathogenesis of glucose intolerance and adiposity.
- MeSH
- adipozita genetika MeSH
- diabetes mellitus 2. typu metabolismus MeSH
- dyslipidemie genetika MeSH
- glukosa metabolismus MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- lipogeneze genetika MeSH
- metabolismus lipidů fyziologie MeSH
- nukleosiddifosfátkinasa genetika metabolismus MeSH
- obezita metabolismus MeSH
- porucha glukózové tolerance genetika metabolismus MeSH
- potkani Sprague-Dawley MeSH
- transkriptom MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
CONTEXT: Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied. OBJECTIVE: To compare changes in pancreatic endocrine function and gut hormones' production during a liquid meal test before and 1 year after adrenalectomy. METHODS: In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins. RESULTS: During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC < 0.01) and pancreatic polypeptide levels (AUC < 0.01) were suppressed in comparison with the postoperative state. Impaired response to the meal was found preoperatively for glucagon-like peptide-1 (GLP-1; AUC P < 0.05), but not glucose-dependent insulinotropic polypepide (GIP; AUC P = 0.21). No significant changes in insulin resistance indices were found, except for the homeostatic model assessment-beta index, an indicator of the function of islet β cells, which negatively correlated with plasma metanephrine (R = -0.66, P < 0.01). CONCLUSIONS: Our study shows suppression of pancreatic α and β cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.
- MeSH
- adrenergní látky škodlivé účinky MeSH
- biologické markery metabolismus MeSH
- dospělí MeSH
- fenotyp MeSH
- feochromocytom komplikace MeSH
- gastrointestinální hormony metabolismus MeSH
- glukagonu podobný peptid 1 metabolismus MeSH
- inkretiny škodlivé účinky MeSH
- jídla MeSH
- krevní glukóza analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory nadledvin komplikace MeSH
- následné studie MeSH
- pankreatické hormony metabolismus MeSH
- porucha glukózové tolerance etiologie metabolismus patologie MeSH
- prognóza MeSH
- prospektivní studie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
AIMS: This study analysed potential sex differences in glucose metabolism of European subjects with different degrees of glucose tolerance impairment. METHODS: Subjects with impaired glucose metabolism, IGM (n = 735), or type 2 diabetes, T2DM (n = 415), were compared to subjects with normal glucose tolerance, NGT (n = 422), with similar BMI. For both males (M) and females (F), 50 years threshold was used for estimation of menopausal/andropausal state. Subjects underwent 75-g OGTT for measurements of insulin sensitivity (OGIS), beta-cell function (insulinogenic index, IGIC), and overall metabolic condition, disposition index (DI). RESULTS: In IGM, OGIS did not change with age in both sexes, whereas marked reduction of IGIC was seen in F (p = 0.0003). In T2DM, again OGIS did not change with age, but M ≥ 50 yrs had reduced IGIC and DI (p < 0.002) compared to M < 50 yrs. CONCLUSIONS: IGM did not reveal relevant changes of insulin resistance with age, but early phase insulin release deteriorated, with higher change in women. T2DM men featured age-related deterioration of glucose metabolism. In women, sex advantage seen in NGT vanished in T2DM, since glucose metabolism was overall not different than in men, both young and elderly.
- MeSH
- diabetes mellitus 2. typu diagnóza metabolismus MeSH
- glukosa metabolismus MeSH
- glukózový toleranční test metody MeSH
- inzulin metabolismus MeSH
- inzulinová rezistence MeSH
- lidé středního věku MeSH
- lidé MeSH
- porucha glukózové tolerance metabolismus MeSH
- sexuální faktory MeSH
- věkové faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is the most common type of dementia, with a prevalence that is rising every year. AD is associated with type 2 diabetes mellitus (T2DM) and insulin resistance, and is therefore sometimes called "type 3 diabetes mellitus". The aim of this study was to examine whether the variants of some candidate genes involved in the development of AD, namely BIN1 (rs744373), CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179), are related to several disorders of glucose metabolism-gestational diabetes (GDM), T2DM and impaired glucose tolerance (IGT). Our study included 550 women with former GDM and 717 control women, 392 patients with T2DM and 180 non-diabetic controls, and 117 patients with IGT and 630 controls with normal glucose tolerance. Genotyping analysis was performed using specially-designed TaqMan assays. No significant associations of the genetic variants rs744373 in BIN1, rs11136000 in CLU, or rs3818361 in CR1 were found with GDM, T2DM or IGT, but rs3851179 in PICALM was associated with an increased risk of GDM. The frequency of the AD risk-associated C allele was significantly higher in the GDM group compared to controls: OR 1.21; 95% CI (1.03-1.44). This finding was not apparent in T2DM and IGT; conversely, the C allele of the PICALM SNP was protective for IGT: OR 0.67; 95% CI (0.51-0.89). This study demonstrates an association between PICALM rs3851179 and GDM as well as IGT. However, elucidation of the possible role of this gene in the pathogenesis of GDM requires further independent studies.
- MeSH
- adaptorové proteiny signální transdukční krev genetika MeSH
- alely MeSH
- Alzheimerova nemoc komplikace genetika MeSH
- běloši genetika MeSH
- diabetes mellitus 2. typu genetika MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- genetická variace MeSH
- genetické asociační studie metody MeSH
- gestační diabetes genetika metabolismus MeSH
- jaderné proteiny krev genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- klusterin krev genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- monomerní proteiny vytvářející klathrin krev genetika MeSH
- nádorové supresorové proteiny krev genetika MeSH
- odds ratio MeSH
- porucha glukózové tolerance genetika metabolismus MeSH
- receptory komplementu 3b krev genetika MeSH
- rizikové faktory MeSH
- senioři MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. METHOD: White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. RESULTS: Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. CONCLUSIONS: We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.
- MeSH
- bílá tuková tkáň cytologie metabolismus MeSH
- dieta s vysokým obsahem tuků MeSH
- energetický metabolismus účinky léků MeSH
- hnědá tuková tkáň cytologie metabolismus MeSH
- inzulinová rezistence * MeSH
- lipidová tělíska metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové proteiny genetika metabolismus MeSH
- obezita metabolismus MeSH
- porucha glukózové tolerance metabolismus MeSH
- termogeneze genetika MeSH
- tukové buňky cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Cushingův syndrom je vzácné onemocnění spojené s významně zvýšenou morbiditou a mortalitou v porovnání s běžnou populací, především v důsledku kardiovaskulárních poruch. Hlavní příčinou jsou pravděpodobně metabolické změny spojené s hypersekrecí kortizolu a zahrnující poruchu glukózové tolerance a diabetes mellitus, obezitu, poruchu metabolismu tuků, katabolismus proteinů a retenci sodíku a vody. Tento článek shrnuje současné poznatky o poruše glukózové homeostázy u Cushingova syndromu a její klinické důsledky.
Cushing's syndrome is a rare disorder associated with significantly increased morbidity and mortality in comparison with general population, mainly due to cardiovascular disorders. Metabolic changes associated with cortisol oversecretion and consisting of glucose intolerance and diabetes, obesity, lipid metabolism disturbances, protein catabolism and sodium and fluid retention, are probably main reason. This article reviews current knowledge about glucose homeostasis disturbances in Cushing's syndrome and its clinical consequences.
- MeSH
- adenom hypofýzy vylučující ACTH farmakoterapie chirurgie MeSH
- Cushingův syndrom * etiologie farmakoterapie metabolismus MeSH
- diabetes mellitus epidemiologie farmakoterapie patofyziologie MeSH
- hypoglykemika terapeutické užití MeSH
- inzulinová rezistence * MeSH
- lidé MeSH
- nádory nadledvin farmakoterapie chirurgie MeSH
- porucha glukózové tolerance metabolismus patofyziologie MeSH
- Check Tag
- lidé MeSH
OBJECTIVE: Besides their role in lipid absorption, bile acids (BAs) can act as signalling molecules. Cholic acid was shown to counteract obesity and associated metabolic disorders in high-fat-diet (cHF)-fed mice while enhancing energy expenditure through induction of mitochondrial uncoupling protein 1 (UCP1) and activation of non-shivering thermogenesis in brown adipose tissue (BAT). In this study, the effects of another natural BA, chenodeoxycholic acid (CDCA), on dietary obesity, UCP1 in both interscapular BAT and in white adipose tissue (brite cells in WAT), were characterized in dietary-obese mice. RESEARCH DESIGN: To induce obesity and associated metabolic disorders, male 2-month-old C57BL/6J mice were fed cHF (35% lipid wt wt(-1), mainly corn oil) for 4 months. Mice were then fed either (i) for 8 weeks with cHF or with cHF with two different doses (0.5%, 1%; wt wt(-1)) of CDCA (8-week reversion); or (ii) for 3 weeks with cHF or with cHF with 1% CDCA, or pair-fed (PF) to match calorie intake of the CDCA mice fed ad libitum; mice on standard chow diet were also used (3-week reversion). RESULTS: In the 8-week reversion, the CDCA intervention resulted in a dose-dependent reduction of obesity, dyslipidaemia and glucose intolerance, which could be largely explained by a transient decrease in food intake. The 3-week reversion revealed mild CDCA-dependent and food intake-independent induction of UCP1-mediated thermogenesis in interscapular BAT, negligible increase of UCP1 in subcutaneous WAT and a shift from carbohydrate to lipid oxidation. CONCLUSIONS: CDCA could reverse obesity in cHF-fed mice, mainly in response to the reduction in food intake, an effect probably occuring but neglected in previous studies using cholic acid. Nevertheless, CDCA-dependent and food intake-independent induction of UCP1 in BAT (but not in WAT) could contribute to the reduction in adiposity and to the stabilization of the lean phenotype.
- MeSH
- bílá tuková tkáň metabolismus MeSH
- dieta s vysokým obsahem tuků MeSH
- energetický metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- iontové kanály metabolismus MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- kyselina chenodeoxycholová metabolismus MeSH
- metabolismus lipidů MeSH
- mitochondriální proteiny metabolismus MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- myši MeSH
- obezita metabolismus MeSH
- oxidační stres MeSH
- porucha glukózové tolerance metabolismus MeSH
- signální transdukce MeSH
- termogeneze * MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diabetes mellitus představuje klinicky nejvýznamnější metabolické onemocnění vyššího věku. U seniorů jde ve většině případů o diabetes 2. typu (nad 70 roků až 95 %). Hyperglykémie ve vysokém věku, i když bude vyšší, může způsobovat často jen atypické a nespecifické příznaky. Prognóza diabetu v seniu bude těsně souviset se stupněm kompenzace a kontrolou současně přítomných rizikových faktorů ischemické choroby srdeční (tj. hypertenze, dyslipidémie, obezity atp.).
Diabetes mellitus represents the most clinically significant metabolic disease in the elderly. Most of the elderly patients suffer from type 2 diabetes (up to 95% among those over 70). Hyperglycaemia can, in patients of advanced age, cause only atypical or non-specific symptoms, even if it is high. The prognosis of diabetes in elderly patients is going to closely depend on the degree of compensation and the level of control maintained over the risk factor of ischemic heart disease (hypertension, dyslipidaemia, obesity).
- MeSH
- diabetes mellitus 2. typu komplikace metabolismus MeSH
- diabetes mellitus * etiologie klasifikace MeSH
- geriatrie MeSH
- inzulinová rezistence MeSH
- komorbidita * MeSH
- krevní glukóza metabolismus účinky léků MeSH
- lidé MeSH
- porucha glukózové tolerance etiologie komplikace metabolismus MeSH
- prevalence MeSH
- rizikové faktory MeSH
- senioři * MeSH
- vnitřní lékařství MeSH
- Check Tag
- lidé MeSH
- senioři * MeSH