scholarly journals Single or combined ablation of peripheral serotonin and p21 limit adipose tissue expansion and metabolic alterations in early adulthood in mice fed a normocaloric diet

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255687
Author(s):  
Enrica Saponara ◽  
Rong Chen ◽  
Theresia Reding ◽  
Richard Zuellig ◽  
Darren C. Henstridge ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Glucose Metabolism ◽  
Tryptophan Hydroxylase ◽  
Kinase Inhibitor ◽  
Early Adulthood ◽  
Tissue Expansion ◽  
Tissue Mass ◽  
Metabolic Alterations ◽  
Novel Treatments

Identifying the fundamental molecular factors that drive weight gain even in the absence of hypercaloric food intake, is crucial to enable development of novel treatments for the global pandemic of obesity. Here we investigated both adipose tissue-specific and systemic events that underlie the physiological weight gain occurring during early adulthood in mice fed a normocaloric diet. In addition, we used three different genetic models to identify molecular factors that promote physiological weight gain during normocaloric and hypercaloric diets. We demonstrated that normal physiological weight gain was accompanied by an increase in adipose tissue mass and the presence of cellular and metabolic signatures typically found during obesity, including adipocyte hypertrophy, macrophage recruitment into visceral fat and perturbed glucose metabolism. At the molecular level, this was associated with an increase in adipose tissue tryptophan hydroxylase 1 (Tph1) transcripts, the key enzyme responsible for the synthesis of peripheral serotonin. Genetic inactivation of Tph1 was sufficient to limit adipose tissue expansion and associated metabolic alterations. Mechanistically, we discovered that Tph1 inactivation resulted in down-regulation of cyclin-dependent kinase inhibitor p21Waf1/Cip1 expression. Single or double ablation of Tph1 and p21 were equally effective in preventing adipocyte expansion and systemic perturbation of glucose metabolism, upon both normocaloric and hypercaloric diets. Our results suggest that serotonin and p21 act as a central molecular determinant of weight gain and associated metabolic alterations, and highlights the potential of targeting these molecules as a pharmacologic approach to prevent the development of obesity.

scholarly journals Growth Hormone Receptor Antagonist Transgenic Mice Are Protected From Hyperinsulinemia and Glucose Intolerance Despite Obesity When Placed on a HF Diet

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 555-564 ◽  
Author(s):  
Tianxu Yang ◽  
Lara A. Householder ◽  
Ellen R. Lubbers ◽  
Edward O. List ◽  
Katie Troike ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Glucose Metabolism ◽  
Receptor Antagonist ◽  
White Adipose Tissue ◽  
Growth Hormone Receptor ◽  
Metabolic Stress ◽  
Tissue Expansion ◽  
Serum Glucose ◽  
Glucose Levels

Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.

Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes

2009 ◽  
Vol 296 (1) ◽  
pp. E121-E131 ◽  
Author(s):  
C. H. Widberg ◽  
F. S. Newell ◽  
A. W. Bachmann ◽  
S. N. Ramnoruth ◽  
M. C. Spelta ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tissue Expansion ◽  
Cell Number ◽  
Fibroblast Growth ◽  
Tissue Mass ◽  
Proliferation And Differentiation ◽  
Adipose Tissue Mass ◽  
Human Preadipocytes

Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF; AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.

scholarly journals Individual housing of male C57BL/6J mice after weaning impairs growth and predisposes for obesity

2019 ◽  
Author(s):  
Lidewij Schipper ◽  
Steffen van Heijningen ◽  
Giorgio Karapetsas ◽  
Eline M. van der Beek ◽  
Gertjan van Dijk
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Energy Intake ◽  
White Adipose Tissue ◽  
Body Weight Gain ◽  
Tissue Mass ◽  
Individual Housing ◽  
Adipose Tissue Mass ◽  
Obesogenic Diet

AbstractIndividual housing from weaning onwards resulted in reduced growth rate during adolescence in male C57Bl/6J mice that were housed individually, while energy intake and energy expenditure were increased compared to socially housed counterparts. At 6 weeks of age, these mice had reduced lean body mass, but significantly higher white adipose tissue mass compared to socially housed mice. Body weight gain of individually housed animals exceeded that of socially housed mice during adulthood, with elevations in both energy intake and expenditure. At 18 weeks of age, individually housed mice showed higher adiposity and higher mRNA expression of UCP-1 in inguinal white adipose tissue. Exposure to an obesogenic diet starting at 6 weeks of age further amplified body weight gain and adipose tissue deposition. This study shows that post-weaning individual housing of male mice results in impaired adolescent growth and higher susceptibility to obesity in adulthood. Mice are widely used to study obesity and cardiometabolic comorbidities. For (metabolic) research models using mice, (social) housing practices should be carefully considered and regarded as a potential confounder due to their modulating effect on metabolic health outcomes.

Effect of adipocyte-derived IGF-I on adipose tissue mass and glucose metabolism in the Berlin Fat Mouse

2018 ◽  
Vol 36 (1-2) ◽  
pp. 78-88 ◽  
Author(s):  
Deike Hesse ◽  
Jan Trost ◽  
Nadine Schäfer ◽  
Kristin Schwerbel ◽  
Andreas Hoeflich ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Tissue Mass ◽  
Igf I ◽  
Adipose Tissue Mass

scholarly journals The cyclin dependent kinase inhibitor Roscovitine reverses diet- induced metabolic disruption in obese mice

2021 ◽  
Author(s):  
Nabil Rabhi ◽  
Kathleen Desevin ◽  
Briana Noel Cortez ◽  
Ryan Hekman ◽  
Jean Z. Lin ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Kinase Inhibitor ◽  
Enrichment Analysis ◽  
Whole Body ◽  
Mitochondrial Activity ◽  
Excess Body Weight ◽  
Pathway Enrichment Analysis ◽  
Brown Adipose ◽  
Metabolic Disruption

Abstract Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Here, we show that roscovitine given to mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at reversing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT.

scholarly journals The cyclin dependent kinase inhibitor Roscovitine prevents diet-induced metabolic disruption in obese mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nabil Rabhi ◽  
Kathleen Desevin ◽  
Briana Noel Cortez ◽  
Ryan Hekman ◽  
Jean Z. Lin ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Kinase Inhibitor ◽  
Whole Body ◽  
Mitochondrial Activity ◽  
Pathway Enrichment Analysis ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Brown Adipose ◽  
Metabolic Disruption

AbstractMost strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Cyclin-dependent kinases have been shown to contribute to obesity and its adverse complications. Here, we show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at preventing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT.

scholarly journals GGEx regulates body weight gain, hyperphagia and adipose tissue mass in obese and diabetic Otsuka Long‐Evans Tokushima fatty (OLETF) rats.

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Yang Sam Jung ◽  
Pei Chin Tsung ◽  
Byoung Chul Kim ◽  
Jong Hoon Kim ◽  
Hoa Jun Seok ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Tissue Mass ◽  
Oletf Rats ◽  
Adipose Tissue Mass ◽  
Long Evans

Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI–Mediated High-Density Lipoprotein Uptake

2021 ◽  
Author(s):  
Hao Xu ◽  
Michael J. Thomas ◽  
Sushma Kaul ◽  
Rachel Kallinger ◽  
Amber B. Ouweneel ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Density Lipoprotein ◽  
Protein Interactions ◽  
Matrix Protein ◽  
Density Lipoprotein ◽  
Tissue Expansion ◽  
High Density ◽  
Extracellular Matrix Protein ◽  
Tissue Mass ◽  
Brown Adipose

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)–mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage. Approach and Results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI– mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI–mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI–mediated HDL-C uptake is unknown. Differentiated cells from Ldlr −/− / Pcpe2 −/− (Pcpe2 −/− ) and Ldlr −/− (control) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake. SR-BI–mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans. Conclusions: Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.

scholarly journals D-Mannose Inhibits Adipogenic Differentiation of Adipose Tissue-Derived Stem Cells via the miR669b/MAPK Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yitong Liu ◽  
Lijia Guo ◽  
Lei Hu ◽  
Chen Xie ◽  
Jingfei Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Mapk Pathway ◽  
Adipogenic Differentiation ◽  
Tissue Expansion ◽  
Mapk Signaling ◽  
Gene Set Enrichment Analysis ◽  
Venn Diagram

The adipogenic differentiation of adipose tissue-derived stem cells (ADSCs) plays an important role in the process of obesity and host metabolism. D-Mannose shows a potential regulating function for fat tissue expansion and glucose metabolism. To explore the mechanisms through which D-mannose affects the adipogenic differentiation of adipose-derived stem cells in vitro, we cultured the ADSCs with adipogenic medium inducement containing D-mannose or glucose as the control. The adipogenic differentiation specific markers Pparg and Fabp4 were determined by real-time PCR. The Oil Red O staining was applied to measure the lipid accumulation. To further explore the mechanisms, microarray analysis was performed to detect the differences between glucose-treated ADSCs (G-ADSCs) and D-mannose-treated ADSCs (M-ADSCs) in the gene expression level. The microarray data were further analyzed by a Venn diagram and Gene Set Enrichment Analysis (GSEA). MicroRNA inhibitor transfection was used to confirm the role of key microRNA. Results. D-Mannose intervention significantly inhibited the adipogenic differentiation of ADSCs, compared with the glucose intervention. Microarray showed that D-mannose increased the expression of miR669b, which was an inhibitor of adipogenesis. In addition, GSEA and western blot suggested that D-mannose suppressed the adipogenic differentiation via inhibiting the MAPK pathway and further inhibited the expression of proteins related to glucose metabolism and tumorigenesis. Conclusion. D-Mannose inhibits adipogenic differentiation of ADSCs via the miR669b/MAPK signaling pathway and may be further involved in the regulation of glucose metabolism and the inhibition of tumorigenesis.

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