Obesity adversely affects bone and fat metabolism in mice and humans. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been shown to improve glucose metabolism and bone homeostasis in obesity. However, the impact of omega-3 PUFAs on bone marrow adipose tissue (BMAT) and bone marrow stromal cell (BMSC) metabolism has not been intensively studied yet. In the present study we demonstrated that omega-3 PUFA supplementation in high fat diet (HFD + F) improved bone parameters, mechanical properties along with decreased BMAT in obese mice when compared to the HFD group. Primary BMSCs isolated from HFD + F mice showed decreased adipocyte and higher osteoblast differentiation with lower senescent phenotype along with decreased osteoclast formation suggesting improved bone marrow microenvironment promoting bone formation in mice. Thus, our study highlights the beneficial effects of omega-3 PUFA-enriched diet on bone and cellular metabolism and its potential use in the treatment of metabolic bone diseases.
- MeSH
- adipozita MeSH
- kosti a kostní tkáň metabolismus MeSH
- kostní dřeň * metabolismus MeSH
- kyseliny mastné omega-3 * farmakologie metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- obezita komplikace prevence a kontrola metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) can progress to more severe stages, such as steatohepatitis and fibrosis. Thermoneutral housing together with high-fat diet promoted NAFLD progression in C57BL/6J mice. Due to possible differences in steatohepatitis development between different C57BL/6 substrains, we examined how thermoneutrality affects NAFLD progression in C57BL/6N mice. METHODS: Male mice were fed standard or high-fat diet for 24 weeks and housed under standard (22°C) or thermoneutral (30°C) conditions. RESULTS: High-fat feeding promoted weight gain and hepatic steatosis, but the effect of thermoneutral environment was not evident. Liver expression of inflammatory markers was increased, with a modest and inconsistent effect of thermoneutral housing; however, histological scores of inflammation and fibrosis were generally low (<1.0), regardless of ambient temperature. In standard diet-fed mice, thermoneutrality increased weight gain, adiposity, and hepatic steatosis, accompanied by elevated de novo lipogenesis and changes in liver metabolome characterized by complex decreases in phospholipids and metabolites involved in urea cycle and oxidative stress defense. CONCLUSION: Thermoneutrality appears to promote NAFLD-associated phenotypes depending on the C57BL/6 substrain and/or the amount of dietary fat.
- MeSH
- bydlení MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- hmotnostní přírůstek MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nealkoholová steatóza jater * metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: Non-shivering thermogenesis (NST) mediated by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) can be activated via the adrenergic system in response to cold or diet, contributing to both thermal and energy homeostasis. Other mechanisms, including metabolism of skeletal muscle, may also be involved in NST. However, relative contribution of these energy dissipating pathways and their adaptability remain a matter of long-standing controversy. METHODS: We used warm-acclimated (30 °C) mice to characterize the effect of an up to 7-day cold acclimation (6 °C; CA) on thermoregulatory thermogenesis, comparing inbred mice with a genetic background conferring resistance (A/J) or susceptibility (C57BL/6 J) to obesity. RESULTS: Both warm-acclimated C57BL/6 J and A/J mice exhibited similar cold endurance, assessed as a capability to maintain core body temperature during acute exposure to cold, which improved in response to CA, resulting in comparable cold endurance and similar induction of UCP1 protein in BAT of mice of both genotypes. Despite this, adrenergic NST in BAT was induced only in C57BL/6 J, not in A/J mice subjected to CA. Cold tolerance phenotype of A/J mice subjected to CA was not based on increased shivering, improved insulation, or changes in physical activity. On the contrary, lipidomic, proteomic and gene expression analyses along with palmitoyl carnitine oxidation and cytochrome c oxidase activity revealed induction of lipid oxidation exclusively in skeletal muscle of A/J mice subjected to CA. These changes appear to be related to skeletal muscle NST, mediated by sarcolipin-induced uncoupling of sarco(endo)plasmic reticulum calcium ATPase pump activity and accentuated by changes in mitochondrial respiratory chain supercomplexes assembly. CONCLUSIONS: Our results suggest that NST in skeletal muscle could be adaptively augmented in the face of insufficient adrenergic NST in BAT, depending on the genetic background of the mice. It may provide both protection from cold and resistance to obesity, more effectively than BAT.
- MeSH
- adrenergní látky metabolismus MeSH
- hnědá tuková tkáň * metabolismus MeSH
- inbrední kmeny myší MeSH
- kosterní svaly metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- obezita metabolismus MeSH
- proteomika * MeSH
- termogeneze fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: The use of thiazolidinediones (TZDs) as insulin sensitizers has been shown to have side effects including increased accumulation of bone marrow adipocytes (BMAds) associated with a higher fracture risk and bone loss. A novel TZD analog MSDC-0602K with low affinity to PPARγ has been developed to reduce adverse effects of TZD therapy. However, the effect of MSDC-0602K on bone phenotype and bone marrow mesenchymal stem cells (BM-MSCs) in relation to obesity has not been intensively studied yet. METHODS: Here, we investigated whether 8-week treatment with MSDC-0602K has a less detrimental effect on bone loss and BM-MSC properties in obese mice in comparison to first generation of TZDs, pioglitazone. Bone parameters (bone microstructure, bone marrow adiposity, bone strength) were examined by μCT and 3-point bending test. Primary BM-MSCs were isolated and measured for osteoblast and adipocyte differentiation. Cellular senescence, bioenergetic profiling, nutrient consumption and insulin signaling were also determined. RESULTS: The findings demonstrate that MSDC-0602K improved bone parameters along with increased proportion of smaller BMAds in tibia of obese mice when compared to pioglitazone. Further, primary BM-MSCs isolated from treated mice and human BM-MSCs revealed decreased adipocyte and higher osteoblast differentiation accompanied with less inflammatory and senescent phenotype induced by MSDC-0602K vs. pioglitazone. These changes were further reflected by increased glycolytic activity differently affecting glutamine and glucose cellular metabolism in MSDC-0602K-treated cells compared to pioglitazone, associated with higher osteogenesis. CONCLUSION: Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases.
- MeSH
- antigen stromálních buněk kostní dřeně metabolismus farmakologie MeSH
- glukosa metabolismus MeSH
- glutamin metabolismus MeSH
- hypoglykemika farmakologie MeSH
- inzulin metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky * metabolismus MeSH
- myši obézní MeSH
- myši MeSH
- obezita farmakoterapie metabolismus MeSH
- pioglitazon metabolismus farmakologie MeSH
- PPAR gama metabolismus MeSH
- spirosloučeniny MeSH
- thiazolidindiony * farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
Prevalence of non-alcoholic fatty liver disease (NAFLD) increases in line with obesity and type 2 diabetes, and there is no approved drug therapy. Polyunsaturated fatty acids of n-3 series (omega-3) are known for their hypolipidaemic and anti-inflammatory effects. Existing clinical trials suggest varying effectiveness of triacylglycerol- or ethyl ester-bound omega-3 in the treatment of NAFLD, without affecting advanced stages such as non-alcoholic steatohepatitis. Preclinical studies suggest that the lipid class used to supplement omega-3 may determine the extent and nature of their effects on metabolism. Phospholipids of marine origin represent an alternative source of omega-3. The aim of this review is to summarise the available evidence on the use of omega-3 phospholipids, primarily in obesity-related NAFLD, and to outline perspectives of their use in the prevention/treatment of NAFLD. A PubMed literature search was conducted in May 2021. In total, 1088 articles were identified, but based on selection criteria, 38 original papers were included in the review. Selected articles describing the potential mechanisms of action of omega-3 phospholipids have also been included. Preclinical evidence clearly indicates that omega-3 phospholipids have strong antisteatotic effects in the liver, which are stronger compared to omega-3 administered as triacylglycerols. Multiple mechanisms are likely involved in the overall antisteatotic effects, involving not only the liver but also adipose tissue and the gut. Robust preclinical evidence for strong antisteatotic effects of omega-3 phospholipids in the liver should be confirmed in clinical trials. Further research is needed on the possible effects of omega-3 phospholipids on advanced NAFLD.
- MeSH
- fosfolipidy MeSH
- kyseliny mastné omega-3 terapeutické užití MeSH
- lidé MeSH
- nealkoholová steatóza jater farmakoterapie etiologie MeSH
- obezita komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Preclinical evidence suggests that n-3 fatty acids EPA and DHA (Omega-3) supplemented as phospholipids (PLs) may be more effective than triacylglycerols (TAGs) in reducing hepatic steatosis. To further test the ability of Omega-3 PLs to alleviate liver steatosis, we used a model of exacerbated non-alcoholic fatty liver disease based on high-fat feeding at thermoneutral temperature. Male C57BL/6N mice were fed for 24 weeks a lard-based diet given either alone (LHF) or supplemented with Omega-3 (30 mg/g diet) as PLs (krill oil; ω3PL) or TAGs (Epax 3000TG concentrate; ω3TG), which had a similar total content of EPA and DHA and their ratio. Substantial levels of TAG accumulation (~250 mg/g) but relatively low inflammation/fibrosis levels were achieved in the livers of control LHF mice. Liver steatosis was reduced by >40% in the ω3PL but not ω3TG group, and plasma ALT levels were markedly reduced (by 68%) in ω3PL mice as well. Krill oil administration also improved hepatic insulin sensitivity, and its effects were associated with high plasma adiponectin levels (150% of LHF mice) along with superior bioavailability of EPA, increased content of alkaloids stachydrine and trigonelline, suppression of lipogenic gene expression, and decreased diacylglycerol levels in the liver. This study reveals that in addition to Omega-3 PLs, other constituents of krill oil, such as alkaloids, may contribute to its strong antisteatotic effects in the liver.
- MeSH
- bydlení zvířat MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- Euphausiacea MeSH
- fosfolipidy farmakologie MeSH
- fyziologie výživy zvířat MeSH
- inzulinová rezistence MeSH
- játra metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nealkoholová steatóza jater etiologie terapie MeSH
- obezita etiologie terapie MeSH
- potravní doplňky * MeSH
- rybí oleje farmakologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs-pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)-regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.
- MeSH
- bílá tuková tkáň metabolismus MeSH
- dieta s vysokým obsahem tuků MeSH
- hypoglykemika farmakologie MeSH
- kyseliny mastné omega-3 aplikace a dávkování farmakologie MeSH
- lipogeneze účinky léků MeSH
- mastné kyseliny metabolismus MeSH
- metabolismus lipidů účinky léků MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- myši MeSH
- obezita farmakoterapie metabolismus MeSH
- pioglitazon farmakologie MeSH
- thiazolidindiony aplikace a dávkování farmakologie MeSH
- triglyceridy metabolismus MeSH
- tukové buňky účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
n-3 polyunsaturated fatty acids (PUFA) can exert beneficial effects on glucose homeostasis, especially in obese rodents. Gut incretin hormones regulate glucose and lipid homeostasis, but their involvement in the above effects is not entirely clear. This study aims to assess the effects of chronic n-3 PUFA administration on the insulin and incretin responses in C57BL/6N obese male mice subjected to oral glucose tolerance test (oGTT) after 8 weeks of feeding a corn-oil-based high-fat diet (cHF). The weight gain and adiposity were partially reduced in mice fed cHF in which some of the corn oil was replaced with n-3 PUFA concentrate containing ∼60% DHA and EPA in a 3 : 1 ratio. In addition, these mice had improved glucose tolerance, which was consistent with an increased insulin response to oral glucose and plasma glucagon-like peptide-1 (GLP-1) levels. While the stimulatory effects of n-3 PUFA on GLP-1 levels could not be attributed to changes in intestinal or plasma dipeptidyl peptidase-4 activity, their beneficial effects on glucose tolerance were abolished when mice were pretreated with the GLP-1 receptor antagonist exendin 9-39. Moreover, chronic n-3 PUFA intake prevented the detrimental effects of cHF feeding on glucose-stimulated insulin secretion in the pancreatic islets. Collectively, our data suggest that n-3 PUFA may modulate postprandial glucose metabolism in obese mice through a GLP-1-based mechanism. The significance of these findings in terms of the effective DHA and EPA ratio of the n-3 PUFA concentrate as well as the effect of n-3 PUFA in humans requires further research.
- MeSH
- aplikace orální MeSH
- dieta s vysokým obsahem tuků MeSH
- glukagonu podobný peptid 1 metabolismus MeSH
- glukózový toleranční test MeSH
- homeostáza MeSH
- inzulin metabolismus MeSH
- krevní glukóza metabolismus MeSH
- kyseliny mastné omega-3 aplikace a dávkování MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- přijímání potravy MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Antisteatotic effects of omega-3 fatty acids (Omega-3) in obese rodents seem to vary depending on the lipid form of their administration. Whether these effects could reflect changes in intestinal metabolism is unknown. Here, we compare Omega-3-containing phospholipids (krill oil; ω3PL-H) and triacylglycerols (ω3TG) in terms of their effects on morphology, gene expression and fatty acid (FA) oxidation in the small intestine. Male C57BL/6N mice were fed for 8 weeks with a high-fat diet (HFD) alone or supplemented with 30 mg/g diet of ω3TG or ω3PL-H. Omega-3 index, reflecting the bioavailability of Omega-3, reached 12.5% and 7.5% in the ω3PL-H and ω3TG groups, respectively. Compared to HFD mice, ω3PL-H but not ω3TG animals had lower body weight gain (-40%), mesenteric adipose tissue (-43%), and hepatic lipid content (-64%). The highest number and expression level of regulated intestinal genes was observed in ω3PL-H mice. The expression of FA ω-oxidation genes was enhanced in both Omega-3-supplemented groups, but gene expression within the FA β-oxidation pathway and functional palmitate oxidation in the proximal ileum was significantly increased only in ω3PL-H mice. In conclusion, enhanced intestinal FA oxidation could contribute to the strong antisteatotic effects of Omega-3 when administered as phospholipids to dietary obese mice.
- MeSH
- dieta s vysokým obsahem tuků * MeSH
- erytrocytární membrána metabolismus MeSH
- Euphausiacea MeSH
- fosfolipidy aplikace a dávkování MeSH
- krevní glukóza analýza MeSH
- kyseliny mastné omega-3 aplikace a dávkování MeSH
- mastné kyseliny metabolismus MeSH
- metabolismus lipidů účinky léků MeSH
- myši obézní MeSH
- oleje MeSH
- oxidace-redukce MeSH
- střeva anatomie a histologie MeSH
- střevní sliznice metabolismus MeSH
- tělesná hmotnost MeSH
- triglyceridy aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
