Regulation Of Adipose Tissue Development Research Articles

CircMEF2C(2, 3) modulates proliferation and adipogenesis of porcine intramuscular preadipocytes by miR-383/671-3p/MEF2C axis

Circular RNA is a special category of non-coding RNA that has emerged as epigenetic regulator of adipose tissue development. However, the mechanism governing intramuscular adipogenesis of circRNA remains largely uncharted. In this study, circMEF2C(2, 3), looped by MEF2C exons 2 and 3, was identified from thepig MEF2C gene. Expression of circMEF2C(2, 3) is upregulated in early stage of intramuscular adipogenesis and muscular tissue of lean pigs (DLY pig). Subsequently, overexpression or knockdown of circMEF2C(2, 3) reflected that it participates in promoting proliferation and inhibiting adipogenic differentiation in porcine intramuscular preadipocytes and murine C3H10T1/2 cells. Mechanically, circMEF2C(2, 3) competitively combined with miR-383 and miR-671-3p to the 3'-UTR of MEF2C, which maintains MEF2C expression in regulating proliferation and adipogenesis. In summary, circMEF2C(2, 3) is a key regulator in the proliferation and adipogenic differentiation of intramuscular adipogenesis, suggesting its potential as a multi-target strategy for adipose development and associated diseases.

Regulation of adipose tissue development and energy metabolism by VEGFB isoforms.

Obesity is caused by imbalanced energy intake and expenditure. The excessive energy intake and storage in adipose tissues is associated with many diseases. Several studies have demonstrated that VEGFB deficiency induces obese phenotypes. However, roles of VEGFB isoforms VEGFB167 and VEGFB186 in adipose tissue development and function are still not clear. In this study, genetic mouse models of adipose-specific VEGFB167 and VEGFB186 overexpression (aP2-Vegfb167tg/+ and aP2-Vegfb186tg/+) were generated and their biologic roles were investigated. On regular chow, adipose-specific VEGFB186 is negatively associated with white adipose tissues (WAT) and positively regulates brown adipose tissues (BAT). VEGFB186 up-regulates energy metabolism and metabolism-associated genes. In contrast, VEGFB167 has nominal roles in adipose development and function. On high fat diet, VEGFB186 expression can reverse the phenotypes of VEGFB deletion. VEGFB186 overexpression up-regulates BAT-associated genes and down-regulates WAT-associated genes. VEGFB186 and VEGFB167 have very distinct roles in regulation of adipose development and energy metabolism. As a key regulator of adipose tissue development and energy metabolism, VEGFB186 may be a target for obesity prevention and treatment.

Adipocyte-specific PIK3C3/VPS34 controls adipogenesis, metabolically-triggered inflammation, insulin resistance, and adaptive thermogenesis in mice

Abstract Interactions between cells of the immune and metabolic systems play critical roles in controlling immune responsiveness and metabolic health. When these interactions are dysregulated, metabolic diseases such as obesity or lipodystrophy may develop. We have focused on cellular processes related to autophagy, a cellular self-degradation process, in controlling interactions between the immune and metabolic systems. In this study, we analyzed mice with an adipocyte-selective deficiency in PIK3C3/VPS34, a key early player in autophagy. These animals showed reduced white and brown adipose tissue (WAT and BAT) with enhanced macrophage infiltration, systemic immune activation, and spontaneous insulin-resistance. The phenotype of these animals bears a striking resemblance with the disease manifestations seen in individuals with lipodystrophy. Mechanistically, we found that conditional Pik3c3-deficiency inhibits adipogenesis in both WAT and BAT by downregulating glucose uptake and fatty acid metabolism, and impairs the thermogenic function of BAT by downregulating the expression of key regulators (Prdm16, Ucp1, and Cidea). Upon acute cold exposure, Pik3c3-deficient mice became cold-sensitive under fasting conditions due to insufficient thermogenesis in BAT. In contrast, these animals exhibited blunted beige fat thermogenesis in subcutaneous WAT in response to administration of a b3-adrenergic receptor agonist. Collectively, our data demonstrate that PIK3C3 is a vital regulator of adipose tissue development, metabolically-triggered inflammation, insulin resistance, and adaptive thermogenesis. Hence, we identify PIK3C3 as a potential therapeutic target for metabolic diseases such as type 2 diabetes.

Matrix Metalloproteinase-11 Promotes Early Mouse Mammary Gland Tumor Growth through Metabolic Reprogramming and Increased IGF1/AKT/FoxO1 Signaling Pathway, Enhanced ER Stress and Alteration in Mitochondrial UPR.

Matrix metalloproteinase 11 (MMP11) is an extracellular proteolytic enzyme belonging to the matrix metalloproteinase (MMP11) family. These proteases are involved in extracellular matrix (ECM) remodeling and activation of latent factors. MMP11 is a negative regulator of adipose tissue development and controls energy metabolism in vivo. In cancer, MMP11 expression is associated with poorer survival, and preclinical studies in mice showed that MMP11 accelerates tumor growth. How the metabolic role of MMP11 contributes to cancer development is poorly understood. To address this issue, we developed a series of preclinical mouse mammary gland tumor models by genetic engineering. Tumor growth was studied in mice either deficient (Loss of Function-LOF) or overexpressing MMP11 (Gain of Function-GOF) crossed with a transgenic model of breast cancer induced by the polyoma middle T antigen (PyMT) driven by the murine mammary tumor virus promoter (MMTV) (MMTV-PyMT). Both GOF and LOF models support roles for MMP11, favoring early tumor growth by increasing proliferation and reducing apoptosis. Of interest, MMP11 promotes Insulin-like Growth Factor-1 (IGF1)/protein kinase B (AKT)/Forkhead box protein O1 (FoxO1) signaling and is associated with a metabolic switch in the tumor, activation of the endoplasmic reticulum stress response, and an alteration in the mitochondrial unfolded protein response with decreased proteasome activity. In addition, high resonance magic angle spinning (HRMAS) metabolomics analysis of tumors from both models established a metabolic signature that favors tumorigenesis when MMP11 is overexpressed. These data support the idea that MMP11 contributes to an adaptive metabolic response, named metabolic flexibility, promoting cancer growth.

β-carotene in Obesity Research: Technical Considerations and Current Status of the Field.

Over the past decades, obesity has become a rising health problem as the accessibility to high calorie, low nutritional value food has increased. Research shows that some bioactive components in fruits and vegetables, such as carotenoids, could contribute to the prevention and treatment of obesity. Some of these carotenoids are responsible for vitamin A production, a hormone-like vitamin with pleiotropic effects in mammals. Among these effects, vitamin A is a potent regulator of adipose tissue development, and is therefore important for obesity. This review focuses on the role of the provitamin A carotenoid β-carotene in human health, emphasizing the mechanisms by which this compound and its derivatives regulate adipocyte biology. It also discusses the physiological relevance of carotenoid accumulation, the implication of the carotenoid-cleaving enzymes, and the technical difficulties and considerations researchers must take when working with these bioactive molecules. Thanks to the broad spectrum of functions carotenoids have in modern nutrition and health, it is necessary to understand their benefits regarding to metabolic diseases such as obesity in order to evaluate their applicability to the medical and pharmaceutical fields.

Distinct Patterns of PPARγ Promoter Usage, Lipid Degradation Activity, and Gene Expression in Subcutaneous Adipose Tissue of Lean and Obese Swine.

Subcutaneous adipose tissue is a loose connective tissue specializing in the regulation of energy storage and metabolization. In domesticated pigs (Sus scrofa), the temporal development of subcutaneous adipose tissue is critical for meat production. However, the regulation of adipose tissue development remains unclear. Here, the subcutaneous adipose tissue development was characterized and compared in lean (Danish-Landrace) and obese (Min) pigs at juvenile and the juvenile-to-adult growth stages. Using RNA sequencing, we profiled the transcriptome of subcutaneous adipose tissue isolated from 4- and 16-week-old pigs and identified 24,718 expressed transcription units. Of them, 6327 genes were differentially expressed between the breeds and/or developmental stages. Compared with obese pigs, upregulated genes in lean pigs showed significant function and pathway enrichment in fatty acid degradation and mitochondrial functions. Further analysis uncovered the distinct usage preferences of the three alternative peroxisome proliferator-activated receptor γ (PPARγ) promoters associated with the development of subcutaneous adipose tissue in both breeds. Transcriptome analysis of subcutaneous adipose tissue in lean and obese pigs suggested that marker-assisted selection of fatty acid degradation and PPARγ signaling pathways could be important directions for future pork quality improvement and modern breeding.

Prostacyclin: A major prostaglandin in the regulation of adipose tissue development.

Prostaglandins (PGs) belong to the group lipid mediators and can act as local hormones. They contain 20 carbon atoms, including a 5-carbon ring, and are biosynthesized from membrane phospholipid derived arachidonic acid through the arachidonate cyclooxygenase (COX) pathway with the help of various terminal synthase enzymes. Prostacyclin (prostaglandin I2 ) is one of the major prostanoids produced with the help of prostacyclin synthase (prostaglandin I2 synthase) enzyme and rapidly hydrolyzed into 6-keto-PGF1α in biological fluids. Obesity indicates an excess of body adiposity, which is globally considered as one of the major health disasters responsible for developing complex pathological situations in the human body. Adipose tissues can produce various PGs, and thus, the level and the molecular activity of these endogenously synthesized PGs are considered critical for the development of obesity. In this regard, the involvement of prostacyclin in adipogenesis has been studied in the last few decades. The current review, along with the background of other related PGs, presents the several molecular aspects of endogenous prostaglandin I2 in adipose tissue development. Especially, the regulation of life cycle of adipocytes, impact on terminal differentiation, activity through prostacyclin receptor (IP), autocrine-paracrine manner, thermogenic adipose tissue remodeling and some future experimental aspects of prostacyclin have been focused upon in this study. This discussion might assist to develop new drug molecules acting on the signaling pathways of prostacyclin and devise therapeutic strategies for treating obesity.

Nutrigenomic regulation of adipose tissue development — role of retinoic acid: A review

To improve the efficiency of animal production, livestock have been extensively selected or managed to reduce fat accumulation and increase lean growth, which reduces intramuscular or marbling fat content. To enhance marbling, a better understanding of the mechanisms regulating adipogenesis is needed. Vitamin A has recently been shown to have a profound impact on all stages of adipogenesis. Retinoic acid, an active metabolite of vitamin A, activates both retinoic acid receptors (RAR) and retinoid X receptors (RXR), inducing epigenetic changes in key regulatory genes governing adipogenesis. Additionally, Vitamin D and folates interact with the retinoic acid receptors to regulate adipogenesis. In this review, we discuss nutritional regulation of adipogenesis, focusing on retinoic acid and its impact on epigenetic modifications of key adipogenic genes.

The proliferation and differentiation of primary pig preadipocytes is suppressed when cultures are incubated at 37°Celsius compared to euthermic conditions in pigs

Given similarities in metabolic parameters and cardiovascular physiology, the pig is well positioned as a biomedical model for metabolic disease and obesity in humans. Better understanding molecular mechanisms governing porcine adipocyte hyperplasia may provide insight into the regulation of adipose tissue development that is useful both when considering the pig as a commodity and when extrapolating porcine data to human disease. Primary cultures of pig stromal-vascular cells have served as a useful tool for investigating factors that regulate preadipocyte proliferation and differentiation. However, such cultures have generally been maintained at 37°C in vitro despite euthermia being 39°C in pigs. To address potential concerns about the physiological relevance of culturing primary pig preadipocytes under what would be hypothermic conditions in vivo, the objective of this study was to investigate the effect of culture temperature on the proliferation and differentiation of pig preadipocytes in primary culture. Culturing primary preadipocytes at 37 rather than 39°C decreases their proliferation rates based upon cleavage of the tetrazolium salt, MTT (P < 0.001), reduction of resazurin (P < 0.001), and daily cell counts (P < 0.001). Likewise, culturing primary porcine preadipocytes at 37°C suppressed their adipogenic potential based upon monitoring adipogenesis morphologically, biochemically, and via the expression of mRNA encoding adipogenic marker genes. Collectively, these data indicate the proliferation and differentiation of primary pig preadipocytes is suppressed when cultures are incubated at 37°C compared to normal body temperature of pigs. This may confound investigation of factors that impact adipocyte hyperplasia in the pig.

Lipin Is a Central Regulator of Adipose Tissue Development and Function in Drosophila melanogaster

Lipins are evolutionarily conserved proteins found from yeasts to humans. Mammalian and yeast lipin proteins have been shown to control gene expression and to enzymatically convert phosphatidate to diacylglycerol, an essential precursor in triacylglcerol (TAG) and phospholipid synthesis. Loss of lipin 1 in the mouse, but not in humans, leads to lipodystrophy and fatty liver disease. Here we show that the single lipin orthologue of Drosophila melanogaster (dLipin) is essential for normal adipose tissue (fat body) development and TAG storage. dLipin mutants are characterized by reductions in larval fat body mass, whole-animal TAG content, and lipid droplet size. Individual cells of the underdeveloped fat body are characterized by increased size and ultrastructural defects affecting cell nuclei, mitochondria, and autophagosomes. Under starvation conditions, dLipin is transcriptionally upregulated and functions to promote survival. Together, these data show that dLipin is a central player in lipid and energy metabolism, and they establish Drosophila as a genetic model for further studies of conserved functions of the lipin family of metabolic regulators.

Galectin-12 Is Required for Adipogenic Signaling and Adipocyte Differentiation

Galectin-12 is a member of the galectin family consisting of beta-galactoside-binding proteins with conserved carbohydrate recognition domains. This protein is preferentially expressed in peripheral blood leukocytes and adipocytes. We previously showed that galectin-12 is induced by cell cycle block at the G(1) phase and causes G(1) arrest when overexpressed (Yang, R.-Y., Hsu, D. K., Yu, L., Ni, J., and Liu, F.-T. (2001) J. Biol. Chem. 276, 20252-20260). Here, we show that the galectin-12 gene is expressed in mouse preadipocytes and is up-regulated when preadipocytes undergo cell cycle arrest, concomitant with acquisition of the competence to undergo differentiation in response to adipogenic hormone stimulation. Following a brief down-regulation 1 day after adipogenic treatment, its expression was once again markedly elevated when cells underwent terminal differentiation. Down-regulation of endogenous galectin-12 expression by RNA interference greatly reduced the expression of the adipogenic transcription factors CCAAT/enhancer-binding protein-beta and -alpha and peroxisome proliferator-activated receptor-gamma and severely suppressed adipocyte differentiation as a result of defective adipogenic signaling. We conclude that galectin-12 is required for signal transduction that conveys hormone stimulation to the induction of adipogenic factors essential for adipocyte differentiation. The findings suggest that galectin-12 is a major regulator of adipose tissue development.

Molecular Cloning of Adipose Tissue-Specific Genes by cDNA Microarray

In an attempt to isolate novel molecules that may play a regulatory role in adipocyte differentiation, we devised an experimental strategy to identify adipose tissue-specific genes by modifying cDNA microarray technique. We used genefilter membranes containing approximately 15,000 rat non-redundant EST clones of which 4,000 EST were representative clones of known genes and 11,000 ESTs were uncharacterized clones. A series of hybridization of genefilter membranes with cDNA probes prepared from various rat tissues and nucleic acids sequence analysis allowed us to identify two adipose-tissue specific genes, adipocyte-specific secretory factor (ADSF) and H-rev107. Verification of tissue-specific expression patterns of these two genes by Northern blot analysis showed that ADSF mRNA is exclusive expressed in adipose tissue and the H-rev107 mRNA is predominantly expressed in adipose tissue. Further analysis of gene expression of ADSF and H-rev107 during 3T3-L1 adipocyte differentiation revealed that the ADSF and H-rev107 gene expression patterns are closely associated with the adipocyte differentiation program, indicating their possible role in the regulation of adipose tissue development. Overall, we demonstrated an application of modified cDNA microarray technique in molecular cloning, resulting in identification of two novel adipose tissue-specific genes. This technique will also be used as a useful tool in identifying novel genes expressed in a tissue-specific manner. (Asian-Aust. J. Anim. Sci. 2003. Vol 16, No. 12 : 1837-1841)

Effects of transforming growth factor-alpha on chicken adipocyte precursor cells in vitro.

The hyperplastic capacity of adipose tissue resides in a group of fibroblast-like adipocyte precursor cells. There is evidence to suggest that their proliferation and differentiation is regulated by insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) but there is less information about other growth factors which may also participate in adipocyte precursor cell hyperplasia. Transforming growth factor-alpha (TGF-alpha) is a 50 amino acid polypeptide which has been shown to stimulate proliferation in both neoplastic and normal cell types acting through the epidermal growth factor (EGF) receptor. We have studied the regulation of DNA synthesis and the activity of lipoprotein lipase by TGF-alpha in chicken adipocyte precursor cells in vitro. Both TGF-alpha and EGF stimulated incorporation of [3H]thymidine into DNA in a dose-dependent manner. TGF-alpha was approximately 180-fold more potent than EGF. Addition of TGF-alpha in combination with IGF-I, TGF-beta 1 or platelet-derived growth factor produced a synergistic increase in DNA synthesis. Short-term incubation with TGF-alpha reduced lipoprotein lipase activity by 23%. These results show that TGF-alpha is a potent mitogen in these adipocyte precursor cells and can inhibit their differentiation in vitro and may participate in the regulation of adipose tissue development in vivo.