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International Journal of Molecular... Jul 2024Osteoporosis is a common bone metabolic disease that causes a heavy social burden and seriously threatens life. Improving osteogenic capacity is necessary to correct... (Review)
Review
Osteoporosis is a common bone metabolic disease that causes a heavy social burden and seriously threatens life. Improving osteogenic capacity is necessary to correct bone mass loss in the treatment of osteoporosis. Osteoblasts are derived from the differentiation of bone marrow mesenchymal stem cells, a process that opposes adipogenic differentiation. The peroxisome proliferator‑activated receptor γ and Wnt/β‑catenin signaling pathways mediate the mutual regulation of osteogenesis and adipogenesis. Lipid substances play an important role in the occurrence and development of osteoporosis. The content and proportion of lipids modulate the activity of immunocytes, mainly macrophages, and the secretion of inflammatory factors, such as IL‑1, IL‑6 and TNF‑α. These inflammatory effectors increase the activity and promote the differentiation of osteoclasts, which leads to bone imbalance and stronger bone resorption. Obesity also decreases the activity of antioxidases and leads to oxidative stress, thereby inhibiting osteogenesis. The present review starts by examining the bidirectional differentiation of BM‑MSCs, describes in detail the mechanism by which lipids affect bone metabolism, and discusses the regulatory role of inflammation and oxidative stress in this process. The review concludes that a reasonable adjustment of the content and proportion of lipids, and the alleviation of inflammatory storms and oxidative damage induced by lipid imbalances, will improve bone mass and treat osteoporosis.
Topics: Humans; Osteoporosis; Lipid Metabolism; Obesity; Animals; Osteogenesis; Oxidative Stress; Mesenchymal Stem Cells; Cell Differentiation
PubMed: 38818830
DOI: 10.3892/ijmm.2024.5385 -
World Journal of Hepatology May 2024Non-alcoholic fatty liver disease (NAFLD) poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits. Its complexity stems... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits. Its complexity stems from genetic predisposition, environmental influences, and metabolic factors. Epigenetic processes govern various cellular functions such as transcription, chromatin structure, and cell division. In NAFLD, these epigenetic tendencies, especially the process of histone methylation, are intricately intertwined with fat accumulation in the liver. Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis. While early-stage NAFLD is reversible, its progression to severe stages becomes almost irreversible. Therefore, early detection and intervention in NAFLD are crucial, and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.
PubMed: 38818286
DOI: 10.4254/wjh.v16.i5.703 -
Animal Nutrition (Zhongguo Xu Mu Shou... Jun 2024In markets for beef and sheep meat, an appropriate level of intramuscular fat (IMF) is highly desirable for meat-eating quality, but strategies to improve it usually... (Review)
Review
In markets for beef and sheep meat, an appropriate level of intramuscular fat (IMF) is highly desirable for meat-eating quality, but strategies to improve it usually lead to an undesirable excess in carcase fat, presenting a major challenge to livestock producers. To solve this problem, we need to understand the partitioning of fat among the major fat depots: IMF, subcutaneous fat (SCF) and visceral fat (VF). In most genotypes of cattle and sheep, the rate of accretion is lower for IMF than for SCF and VF, so genetic selection for a high level of IMF, or the use of an increased dietary energy supply to promote IMF deposition, will increase overall fatness and feed costs. On the other hand, feeding postnatal calves with excessive concentrates promotes IMF deposition, so a nutritional strategy is feasible. With genetic strategies, several problems arise: 1) positive genetic correlations between IMF, SCF and VF differ among genotypes in both cattle and sheep; 2) genotypes appear to have specific, characteristic rates of accretion of IMF during periods of growth and fattening; 3) most breeds of cattle and sheep naturally produce meat with relatively low levels of IMF, but IMF does vary substantially among individuals and breeds so progress is possible through accurate measurement of IMF. Therefore, an essential prerequisite for selection will be knowledge of the genetic correlations and fat accretion rates for each genotype. Currently, selection for IMF is based on existing technology that directly measures IMF in the progeny or siblings, or estimates IMF in live animals. New technology is needed to permit the simultaneous measurement of SCF and IMF in the field, thus opening up the possibility of accurate selection, particularly for fat partitioning in live animals. Specifically, there would be great value in detecting individuals with an IMF advantage at an early age so the generation interval could be shortened and genetic gain accelerated. Genetic gain would also be greatly aided if we could select for genes that control adipogenesis and lipogenesis and are also differentially expressed in the various depots.
PubMed: 38812494
DOI: 10.1016/j.aninu.2024.03.003 -
Biomedicine & Pharmacotherapy =... Jul 2024Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis....
Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis. Endosome-associated trafficking regulator 1 (ENTR1) has been found to interact with different proteins in pathophysiology, but its exact role in adipogenesis is not yet understood. This research aimed to explore the role of ENTR1 in adipogenesis and to discover a new small molecule that targets ENTR1 for evaluating its effectiveness in treating hyperlipidemia-induced osteoporosis. We found that ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain- and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression, thereby elevating adipogenic markers including C/EBPα and LDLR. Therapeutically, AN698/40746067 attenuated adipogenesis by targeting ENTR1 to suppress PPARγ. In vivo, AN698/40746067 reduced bone marrow adiposity and bone loss, as well as prevented lipogenesis-related obesity, inflammation, steatohepatitis, and abnormal serum lipid levels during hyperlipidemia. Together, these findings suggest that ENTR1 facilitates adipogenesis by PPARγ involved in BMSCs' differentiation, and targeted inhibition of ENTR1 by AN698/40746067 may offer a promising therapy for addressing lipogenesis-related challenges and alleviating osteoporosis following hyperlipidemia.
Topics: Animals; Hyperlipidemias; Osteoporosis; PPAR gamma; Adipogenesis; Adiposity; Mice, Inbred C57BL; Mice; Mesenchymal Stem Cells; Male; Bone Marrow; Endosomal Sorting Complexes Required for Transport
PubMed: 38810405
DOI: 10.1016/j.biopha.2024.116843 -
Journal of Orthopaedic Translation May 2024Osteoporosis is one of the most common bone diseases in middle-aged and elderly populations worldwide. The development of new drugs to treat the disease is a key focus...
BACKGROUND
Osteoporosis is one of the most common bone diseases in middle-aged and elderly populations worldwide. The development of new drugs to treat the disease is a key focus of research. Current treatments for osteoporosis are mainly directed at promoting osteoblasts and inhibiting osteoclasts. However, there is currently no ideal approach for osteoporosis treatment. l-arginine is a semi-essential amino acid involved in a number of cellular processes, including nitric production, protein biosynthesis, and immune responses. We previously reported that l-arginine-derived compounds can play a regulatory role in bone homeostasis.
PURPOSE
To investigate the specific effect of l-arginine on bone homeostasis.
METHODS
Mildly aged and ovariectomized mouse models were used to study the effects of l-arginine on osteogenesis and angiogenesis, assessed by micro-computed tomography and immunostaining of bone tissue. The effect of l-arginine on osteogenesis, angiogenesis, and adipogenesis was further studied in vitro using osteoblasts obtained from cranial cap bone, endothelial cells, and an adipogenic cell line. Specific methods to assess these processes included lipid staining, cell migration, tube-forming, and wound-healing assays. Protein and mRNA expression was determined for select biomarkers.
RESULTS
We found that l-arginine attenuated bone loss and promoted osteogenesis and angiogenesis. l-arginine increased the activity of vascular endothelial cells, whereas it inhibited adipogenesis in vitro. In addition, we found that l-arginine altered the expression of PINK1/Parkin and Bnip3 in the mitochondria of osteoblast-lineage and endothelial cells, thereby promoting mitophagy and protecting cells from ROS. Similarly, l-arginine treatment effectively ameliorated osteoporosis in an ovariectomized mouse model.
CONCLUSION
l-arginine promotes angio-osteogenesis, and inhibits adipogenesis, effects mediated by the PINK1/Parkin- and Bnip3-mediated mitophagy.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
L-arginine supplementation may be an effective adjunct therapy in the treatment of osteoporosis.
PubMed: 38808262
DOI: 10.1016/j.jot.2024.03.003 -
MedComm Jun 2024Cancer cachexia is a multifactorial condition that contributes to the death of about 20% of cancer patients. It has the potential to cause weight loss, reduction in...
Cancer cachexia is a multifactorial condition that contributes to the death of about 20% of cancer patients. It has the potential to cause weight loss, reduction in muscle mass, and loss of fat tissue, significantly lowering the quality of life. Currently, there are no approved drugs for cancer cachexia. Here, we have explored the possible impact of brassinin (BSN) on cancer cachexia under in vitro and in vivo settings. After differentiation, C2C12 and 3T3-L1 cells were incubated with colorectal carcinoma cells conditioned media or BSN. For preclinical studies, mice were injected with HT-29 cells followed by intraperitoneal administration of BSN, and muscle and adipose tissues were evaluated by Western blotting and hematoxylin and eosin staining. BSN effectively suppressed muscle atrophy by down-regulating the levels of Muscle RING-finger protein-1 and Atrogin-1, while also increasing the expression of myosin heavy chain in cachexia-induced-C2C12 myotubes. The induction of adipogenesis by BSN prevented adipocyte atrophy in cachexia-induced 3T3-L1 adipocytes. We also noted that BSN disrupted the interaction between COX-2 and signaling transducer and activator of transcription 3 (STAT3) promoter, leading to down-regulation of STAT3 activation. Moreover, it was found that BSN inhibited weight loss in mice and demonstrated anti-cachexic effects. Overall, our observations indicate that BSN can attenuate cancer cachexia through diverse mechanisms.
PubMed: 38807976
DOI: 10.1002/mco2.558 -
Biomedicine & Pharmacotherapy =... Jul 2024The overstoring of surplus calories in mature adipocytes causes obesity and abnormal metabolic activity. The anti-obesity effect of a Celosia cristata (CC) total flower...
BACKGROUND
The overstoring of surplus calories in mature adipocytes causes obesity and abnormal metabolic activity. The anti-obesity effect of a Celosia cristata (CC) total flower extract was assessed in vitro, using 3T3-L1 pre-adipocytes and mouse adipose-derived stem cells (ADSCs), and in vivo, using high-fat diet (HFD)-treated C57BL/6 male mice.
METHODS
CC extract was co-incubated during adipogenesis in both 3T3-L1 cells and ADSCs. After differentiation, lipid droplets were assessed by oil red O staining, adipogenesis and lipolytic factors were evaluated, and intracellular triglyceride and glycerol concentrations were analyzed. For in vivo experiments, histomorphological analysis, mRNA expression levels of adipogenic and lipolytic factors in adipose tissue, blood plasma analysis, metabolic profiles were investigated.
RESULTS
CC treatment significantly prevented adipocyte differentiation and lipid droplet accumulation, reducing adipogenesis-related factors and increasing lipolysis-related factors. Consequently, the intracellular triacylglycerol content was diminished, whereas the glycerol concentration in the cell supernatant increased. Mice fed an HFD supplemented with the CC extract exhibited decreased HFD-induced weight gain with metabolic abnormalities such as intrahepatic lipid accumulation and adipocyte hypertrophy. Improved glucose utilization and insulin sensitivity were observed, accompanied by the amelioration of metabolic disturbances, including alterations in liver enzymes and lipid profiles, in CC-treated mice. Moreover, the CC extract helped restore the disrupted energy metabolism induced by the HFD, based on a metabolic animal monitoring system.
CONCLUSION
This study suggests that CC total flower extract is a potential natural herbal supplement for the prevention and management of obesity.
Topics: Animals; Plant Extracts; Male; Mice; 3T3-L1 Cells; Mice, Inbred C57BL; Anti-Obesity Agents; Flowers; Adipogenesis; Obesity; Diet, High-Fat; Adipocytes; Celosia; Adipose Tissue; Lipid Metabolism; Lipolysis; Cell Differentiation
PubMed: 38805969
DOI: 10.1016/j.biopha.2024.116799 -
STAR Protocols Jun 20243T3-L1 is a model cell line which can be differentiated from preadipocytes into mature adipocytes. Here, we present a protocol for changing gene expression in 3T3-L1...
3T3-L1 is a model cell line which can be differentiated from preadipocytes into mature adipocytes. Here, we present a protocol for changing gene expression in 3T3-L1 (pre)adipocytes using small interfering RNA (siRNA)-mediated knockdown. We describe steps to perform the knockdown of a certain gene prior to differentiation (day 4) to analyze the impact on adipogenesis. We then detail procedures for knockdown on day 8 of differentiation to study the role of a certain gene in mature adipocyte function. For complete details on the use and execution of this protocol, please refer to Kaczmarek et al..
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes; RNA, Small Interfering; Gene Knockdown Techniques; Adipogenesis; Cell Differentiation; Gene Expression
PubMed: 38805394
DOI: 10.1016/j.xpro.2024.103075 -
Frontiers in Nutrition 2024The branched-chain amino acids (BCAAs) are essential to mammalian growth and development but aberrantly elevated in obesity and diabetes. Each BCAA has an independent...
INTRODUCTION
The branched-chain amino acids (BCAAs) are essential to mammalian growth and development but aberrantly elevated in obesity and diabetes. Each BCAA has an independent and specific physio-biochemical effect on the host. However, the exact molecular mechanism of the detrimental effect of valine on metabolic health remains largely unknown.
METHODS AND RESULTS
This study showed that for lean mice treated with valine, the hepatic lipid metabolism and adipogenesis were enhanced, and the villus height and crypt depth of the ileum were significantly increased. Transcriptome profiling on white and brown adipose tissues revealed that valine disturbed multiple signaling pathways (e.g., inflammation and fatty acid metabolism). Integrative cecal metagenome and metabolome analyses found that abundances of decreased, but and increased, respectively; and 87 differential metabolites were enriched in several molecular pathways (e.g., inflammation and lipid and bile acid metabolism). Furthermore, abundances of two metabolites (stercobilin and 3-IAA), proteins (AMPK/pAMPK and SCD1), and inflammation and adipogenesis-related genes were validated.
DISCUSSION
Valine treatment affects the intestinal microbiota and metabolite compositions, induces gut inflammation, and aggravates hepatic lipid deposition and adipogenesis. Our findings provide novel insights into and resources for further exploring the molecular mechanism and biological function of valine on lipid metabolism.
PubMed: 38803448
DOI: 10.3389/fnut.2024.1379390 -
Research Square May 2024Previous studies have identified G protein-coupled receptor (GPCR) kinase 5 (GRK5) as a genetic factor contributing to obesity pathogenesis, but the underlying mechanism...
Previous studies have identified G protein-coupled receptor (GPCR) kinase 5 (GRK5) as a genetic factor contributing to obesity pathogenesis, but the underlying mechanism remains unclear. We demonstrate here that Grk5 mRNA is more abundant in stromal vascular fractions of mouse white adipose tissue, the fraction that contains adipose progenitor cells, or committed pre-adipocytes, than in adipocyte fractions. Thus, we generated a GRK5 knockout (KO) 3T3-L1 pre-adipocyte to further investigate the mechanistic role of GRK5 in regulating adipocyte differentiation. During adipogenic stimulation, GRK5 KO pre-adipocytes were unable to achieve mature adipocyte morphology and lipid accumulation compared to wildtype cells coupled with suppressed adipogenic and lipogenic gene expression. Beside GPCR signaling, RNA sequencing and pathway analysis identified insulin-like growth factor 1 (IGF-1) signaling to be one of the top 5 significantly dysregulated pathways in GRK5 KO cells. GRK5 KO cells also displayed decreased insulin-stimulated ERK phosphorylation, a downstream target of insulin-stimulated IGF-1 receptor activation, suggesting that GRK5 acts through this critical pathway to impact 3T3-L1 adipocyte differentiation. To find a more translational approach, we identified a new small molecule GRK5 inhibitor that was able to reduce 3T3-L1 adipogenesis. These data suggest that GRK5 is required for adipocyte differentiation through IGF-1 receptor/ERK activation and may be a promising translational target for obesity.
PubMed: 38798474
DOI: 10.21203/rs.3.rs-4360297/v1