• ATP-citrate lyase
• brown adipose tissue
• fatty acid synthase
• lipogenic enzymes
• mRNA expression
• malic enzyme
• subcutaneous adipose tissue
• uncoupling protein 1

• Animals
• Lipogenesis/genetics
• Rats
• Subcutaneous Fat/metabolism
• Rats, Wistar
• ATP Citrate (pro-S)-Lyase/metabolism
• ATP Citrate (pro-S)-Lyase/genetics
• Male
• Uncoupling Protein 1/metabolism
• Uncoupling Protein 1/genetics
• Malate Dehydrogenase/metabolism
• Malate Dehydrogenase/genetics
• Fatty Acid Synthases/metabolism
• Fatty Acid Synthases/genetics
• RNA, Messenger/metabolism
• RNA, Messenger/genetics

• Brown adipose tissue
• Browning of adipose tissue
• Diabetes mellitus
• Genes
• Obesity
• Proteins
• White adipose tissue

• Humans
• Adipose Tissue, Brown/metabolism
• Diabetes Mellitus, Type 2/metabolism
• Obesity/metabolism
• Adiposity
• Transcription Factors/metabolism
• Adipose Tissue, White/metabolism
• Thermogenesis/genetics

• Cdk6
• Runx1
• obesity
• progenitors
• stem cells

• R01 DK134534 NIDDK NIH HHS
• U.S. Army Medical Research Acquisition Activity

• Biochemistry
• Biological sciences
• Molecular Genetics

• Adipose tissue
• Rheb
• White adipocytes
• cAMP/PPARγ pathway
• miR-182-5p

• Adipogenic differentiation
• BODIPY
• Cell cycle
• Patient-derived stem cells
• RB1 mutation
• UCP1

• Anxiety-like behavior
• Beigeing
• Brown adipose tissue
• Glucose metabolism
• Insulin secretion
• Neurobehavior
• SNAP25
• Steroidogenesis
• White adipose tissue

• Animals
• Behavior, Animal
• Female
• Gonadal Steroid Hormones/metabolism
• Homeostasis
• Insulin Resistance
• Male
• Metabolic Diseases/etiology
• Metabolic Diseases/metabolism
• Metabolic Diseases/pathology
• Mice
• Mice, Inbred C3H
• Mutation
• Synaptic Transmission
• Synaptosomal-Associated Protein 25/genetics
• Synaptosomal-Associated Protein 25/physiology

• I01 BX000398 BLRD VA
• I01 BX001923 BLRD VA
• IK6 BX004200 BLRD VA
• P30 DK116074 NIDDK NIH HHS

Fibroblast growth factor 2 (FGF2) has been reported to play divergent roles in white adipogenic differentiation, however, whether it regulates thermogenesis of fat tissues remains largely unknown. We therefore aimed to investigate the effect of FGF2 on fat thermogenesis and elucidate the underlying mechanisms.

FGF2-KO and wild-type (WT) mice were fed with chow diet and high-fat diet (HFD) for 14 weeks. The brown and white fat mass, thermogenic capability, respiratory exchange ratio, and hepatic fat deposition were determined. In vitro experiments were conducted to compare the thermogenic ability of FGF2-KO- with WT-derived brown and white adipocytes. Exogenous FGF2 was supplemented to in vitro-cultured WT brown and ISO-induced beige adipocytes. The FGFR inhibitor, PPARγ agonist, and PGC-1α expression lentivirus were used with the aid of technologies including Co-IP, ChIP, and luciferase reporter assay to elucidate the mechanisms underlying the FGF2 regulation of thermogenesis.

FGF2 gene disruption results in increased thermogenic capability in both brown and beige fat, supporting by increased UCP1 expression, enhanced respiratory exchange ratio, and elevated thermogenic potential in response to cold exposure. Thus, the deletion of FGF2 protects mice from high fat-induced adiposity and hepatic steatosis. Mechanistically, in vitro investigations indicated FGF2 acts in autocrine/paracrine fashions. Exogenous FGF2 supplementation inhibits both PGC-1α and PPARγ expression, leading to suppression of UCP1 expression in brown and beige adipocytes.

These findings demonstrate that FGF2 is a novel thermogenic regulator, suggesting a viable potential strategy for using FGF2-selective inhibitors in combat adiposity and associated hepatic steatosis.

•

FGF2-KO mice show potentiated stimulation on thermogenic capability under both basal and cold challenge stimulation.

• Brown and beige fat
• Fibroblast growth factor 2 (FGF2)
• PGC-1α
• PPARγ
• Thermogenesis

• Animals
• Humans
• Membrane Proteins/metabolism
• Nuclear Envelope/metabolism
• Receptors, Cytoplasmic and Nuclear/metabolism
• Lamin B Receptor

We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C–C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A’s effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.

• adipocytes
• atheroprotection
• atherosclerosis
• brown adipose tissue
• browning
• cold exposure
• non-shivering thermogenesis
• white adipose tissue
• β3-adrenergic stimulation

• 310030_182573 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

The retinoblastoma gene product (pRb) is a chromatin-associated protein that can either suppress or promote activity of key regulators of tissue-specific differentiation. We found that twelve weeks after transfection of the exogenous active (ΔB/X and Δр34) or inactive (ΔS/N) forms of RB into the 10T1/2 mesenchymal stem cells and clonal selection not a single cell line did contain exogenous RB, despite being G-418 resistant. However, the consequences of the transient production of exogenous RB had different effects on the cell fate. The ΔB/X and Δр34 cells transfected with active form of RB showed elevated levels of inducible adipocyte differentiation (AD). On the contrary, the ΔS/N cells transfected with inactive RB mutant were insensitive to induction of AD associated with abolishing of expression of the PPARγ2. Additionally, the PPARγ2 promoter in undifferentiated ΔS/N cells was hypermethylated, but all except −60 position CpG became mostly demethylated after cells exposure to AD. We conclude that while transient expression of inactive exogenous RB induces long term epigenetic alterations that prevent adipogenesis, production of active exogenous RBs results in an AD-promoting epigenetic state. These results indicate that pRb is involved in the establishment of hereditary epigenetic memory at least by creating a methylation pattern of PPARγ2.

• AD, adipogenic differentiation
• Adipogenic differentiation
• DNA methyltransferase 1
• DNMT1, DNA methyltransferase 1
• MSCs
• MSCs, mesenchymal stem cells
• Mesenchymal stem cells
• RB
• RB, retinoblastoma susceptibility gene
• Retinoblastoma susceptibility gene
• pRb, RB product

• adipocytes
• beige
• brite
• brown
• diabetes
• obesity
• plasticity
• thermogenesis
• transdifferentiation

• Brown adipose tissue
• Cancer
• Cold stress
• Epigenetics
• Genetics
• Thermogenesis

Obesity is now a widespread disorder, and its prevalence has become a critical concern worldwide, due to its association with common co-morbidities like cancer, cardiovascular diseases and diabetes. Adipose tissue is an endocrine organ and therefore plays a critical role in the survival of an individual, but its dysfunction or excess is directly linked to obesity. The journey from multipotent mesenchymal stem cells to the formation of mature adipocytes is a well-orchestrated program which requires the expression of several genes, their transcriptional factors, and signaling intermediates from numerous pathways. Understanding all the intricacies of adipogenesis is vital if we are to counter the current epidemic of obesity because the limited understanding of these intricacies is the main barrier to the development of potent therapeutic strategies against obesity. In particular, AMP-Activated Protein Kinase (AMPK) plays a crucial role in regulating adipogenesis – it is arguably the central cellular energy regulation protein of the body. Since AMPK promotes the development of brown adipose tissue over that of white adipose tissue, special attention has been given to its role in adipose tissue development in recent years. In this review, we describe the molecular mechanisms involved in adipogenesis, the role of signaling pathways and the substantial role of activated AMPK in the inhibition of adiposity, concluding with observations which will support the development of novel chemotherapies against obesity epidemics.

• AMPK
• BAT
• WAT
• adipogenesis
• beige/brite adipocytes
• obesity

• Adipogenesis
• Beige adipocytes
• FTO
• Irx3
• Obesity

• Adipocytes, Beige/physiology
• Adipogenesis/genetics
• Animals
• Cell Differentiation/genetics
• Cell Lineage/genetics
• Cells, Cultured
• Gene Expression Regulation, Developmental
• Gene Knockdown Techniques
• Homeodomain Proteins/genetics
• Homeodomain Proteins/physiology
• Humans
• Mice
• Transcription Factors/genetics
• Transcription Factors/physiology

• 293574 European Research Council

β-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the β3-adrenergic receptor (β3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses β3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.

Beta3-adrenergic receptor (b3-AR) signaling in response to cold activates adipose tissue thermogenesis. Here the authors identify the transcription factor FoxP1 as a direct negative regulator of b3-AR expression and show that loss of FoxP1 leads to enhanced development of thermogenic adipose tissue.

• RB1
• SNP
• abdominal fat
• chicken
• gene expression
• intron

• Abdominal Fat/metabolism
• Adiposity
• Alleles
• Animals
• Avian Proteins/genetics
• Avian Proteins/metabolism
• Binding Sites
• Chickens/genetics
• Chickens/growth & development
• Chickens/metabolism
• Introns
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Polymorphism, Single Nucleotide
• Protein Binding
• Retinoblastoma Protein/genetics
• Retinoblastoma Protein/metabolism
• SOX Transcription Factors/genetics
• SOX Transcription Factors/metabolism

• Brown adipocytes
• Brown fat
• Cell lines

• Adipocytes, Brown
• Adipose Tissue, Brown
• Animals
• Cell Differentiation
• Cell Line
• Thermogenesis/physiology

High protein diets have become popular for body weight maintenance and weight loss despite controversies regarding efficacy and safety. Although both weight gain and weight loss are determined by energy consumption and expenditure, data from rodent trials consistently demonstrate that the protein:carbohydrate ratio in high fat diets strongly influences body and fat mass gain per calorie eaten. Here, we review data from rodent trials examining how high protein diets may modulate energy metabolism and the mechanisms by which energy may be dissipated. We discuss the possible role of activating brown and so-called beige/BRITE adipocytes including non-canonical UCP1-independent thermogenesis and futile cycles, where two opposing metabolic pathways are operating simultaneously. We further review data on how the gut microbiota may affect energy expenditure. Results from human and rodent trials demonstrate that human trials are less consistent than rodent trials, where casein is used almost exclusively as the protein source. The lack of consistency in results from human trials may relate to the specific design of human trials, the possible distinct impact of different protein sources, and/or the differences in the efficiency of high protein diets to attenuate obesity development in lean subjects vs. promoting weight loss in obese subjects.

• brown adipose tissue (BAT)
• diet
• futile cycles
• high protein diets
• human
• mouse
• obesity
• weight loss

A causal obesity risk variant in the FTO locus was recently shown to inhibit adipocyte thermogenesis via increased adipose expression of the homeobox transcription factors IRX3 and IRX5. However, causal effects of IRX5 on fat storage remain to be shown in vivo, and discovery of downstream mediators may open new therapeutic avenues.

17 WT and 13 Irx5 knockout (KO) mice were fed low-fat control (Ctr) or high-fat (HF) diet for 10 weeks. Body weight, energy intake and fat mass were measured. Irx5-dependent gene expression was explored by transcriptome analysis of epididymal white adipose tissue (eWAT), confirmatory obesity-dependent expression in human adipocytes in vivo, and in vitro knock-down, overexpression and transcriptional activation assays.

Irx5 knock-out mice weighed less, had diminished fat mass, and were protected from diet-induced fat accumulation. Key adipose mitochondrial genes Pparγ coactivator 1-alpha (Pgc-1α) and uncoupling protein 1 (Ucp1) were upregulated, and a gene network centered on amyloid precursor protein (App) was downregulated in adipose tissue of knock-out mice and in isolated mouse adipocytes with stable Irx5 knock-down. An APP-centered network was also enriched in isolated adipocytes from obese compared to lean humans. IRX5 overexpression increased APP promoter activity and both IRX5 and APP inhibited transactivation of PGC-1α and UCP1. Knock-down of Irx5 or App increased mitochondrial respiration in adipocytes.

Irx5-KO mice were protected from obesity and this can partially be attributed to reduced adipose App and improved mitochondrial respiration. This novel Irx5-App pathway in adipose tissue is a possible therapeutic entry point against obesity.

• adipose tissue
• development
• lineage tracing
• metabolic syndrome
• obesity

• Adipose Tissue/growth & development
• Adipose Tissue/metabolism
• Adipose Tissue/pathology
• Adipose Tissue/physiology
• Aging/pathology
• Animals
• Apoptosis
• Humans
• Obesity/pathology

Class I histone deacetylase inhibitors (HDACis) enhance whole body energy expenditure and attenuate high fat diet-induced insulin resistance. However, it is not clear whether this is exerted directly through activating brown fat thermogenesis. Here, we find that pan-HDACi TSA exerts paradoxical effects on brown fat gene expression, as it inhibits the expression of Ucp1, Pparγ and Prdm16 in brown adipocytes, while promoting the expression of other brown fat-specific genes such as Pgc1α, Pgc1β, Acox1 and Cidea. Further studies indicate that class I HDACi MS-275 significantly increases; whereas class II HDACi MC-1568 markedly reduces, the expression of Ucp1 and other brown fat-specific genes in treated brown adipocytes. ChIP assay reveals an enhanced H3 acetylation at the Pgc1α promoter in MS-275-treated brown adipocytes; whereas the effect of MC-1568 is associated with up-regulation of retinoblastoma protein (Rb) and an enhanced acetylation of H3K27 at the Rb promoter. Loss of function studies indicate that Pgc1α up-regulation largely mediates the stimulatory effect of class I HDACis on the thermogenic program, whereas up-regulation of Rb may be responsible for the inhibitory effect of class II HDACis. Thus, our data suggest that class I and II HDACis have differential effects on brown fat thermogenic gene expression.

• BAT
• FOG-2
• GATA
• WAT
• adipogenesis
• obesity
• retinoblastoma

• Adipocytes
• Adipose stem cells
• Insulin
• Obesity
• Thermogenesis
• Uncoupling protein

• PPARγ
• PRDM16
• UCP1
• adipocyte browning
• adipose tissue
• beige fat
• obesity

• Beige adipocyte
• White adipocyte
• Zfp423

• Beige fat
• Brown fat
• Human fat
• Obesity
• Thermogenesis

• Intermediate Filament
• Mouse Model
• Nuclear Lamina
• Pancreas
• Partial Lipodystrophy

• Ebf2
• Prdm16
• Ucp1
• beige adipocyte
• cachexia

Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6^−/− mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.

Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.

• Adipose tissue
• CDKs
• Cell cycle
• Cyclins
• Insulin resistance
• Metabolism
• Obesity

• Adipose Tissue/metabolism
• Animals
• Cell Cycle Checkpoints
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Cyclin-Dependent Kinase Inhibitor Proteins/genetics
• Cyclin-Dependent Kinase Inhibitor Proteins/metabolism
• Cyclin-Dependent Kinases/genetics
• Cyclin-Dependent Kinases/metabolism
• Cyclins/genetics
• Cyclins/metabolism
• E2F Transcription Factors/genetics
• E2F Transcription Factors/metabolism
• Energy Metabolism
• Humans

• Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Adipogenesis is regulated by a complex network of molecules, including fibroblast growth factors. Keratinocyte growth factor (KGF) has been previously reported to promote proliferation on rat preadipocytes, although the expression of its specific receptor, FGFR2-IIIb/KGFR, is not actually detected in mesenchymal cells. Here, we demonstrate that human adipose-derived stem cells (ASCs) show increased expression of KGF during adipogenic differentiation, especially in the early steps. Moreover, KGF is able to induce transient activation of ERK and p38 MAPK pathways in these cells. Furthermore, KGF promotes ASC differentiation and supports the activation of differentiation pathways, such as those of PI3K/Akt and the retinoblastoma protein (Rb). Notably, we observed only a low amount of FGFR2-IIIb in ASCs, which seems not to be responsible for KGF activity. Here, we demonstrate for the first time that Neuropilin 1 (NRP1), a transmembrane glycoprotein expressed in ASCs acting as a coreceptor for some growth factors, is responsible for KGF-dependent pathway activation in these cells. Our study contributes to clarify the molecular bases of human adipogenesis, demonstrating a role of KGF in the early steps of this process, and points out a role of NRP1 as a previously unknown mediator of KGF action in ASCs.

Inhibition of Akt-mTOR signaling protects from obesity and extends life span in animals. In the present study, we analyse the impact of the small GTPase, GTP-binding RAS-like 3 (DIRAS3), a recently identified weight-loss target gene, on cellular senescence in adipose stromal/progenitor cells (ASCs) derived from human subcutaneous white adipose tissue (sWAT). We demonstrate that DIRAS3 knock-down (KD) in ASCs induces activation of Akt-mTOR signaling and proliferation arrest. DIRAS3 KD ASCs lose the potential to form colonies and are negative for Ki-67. Moreover, silencing of DIRAS3 results in a premature senescence phenotype. This is characterized by senescence-associated β-galactosidase positive enlarged ASCs containing increased p16^INK4A level and activated retinoblastoma protein. DIRAS3 KD ASCs form senescence-associated heterochromatic foci as shown by increased level of γ-H2A.X positive foci. Furthermore, these cells express a senescence-associated secretory phenotype characterized by increased interleukin-8 secretion. Human DIRAS3 KD ASCs develop also a senescence phenotype in sWAT of SCID mice. Finally, we show that DIRAS3 KD in ASCs stimulates both adipogenic differentiation and premature senescence. In conclusion, our data suggest that silencing of DIRAS3 in ASCs and subsequently hyper-activation of Akt-mTOR drives adipogenesis and premature senescence. Moreover, differentiating ASCs and/or mature adipocytes may acquire features of cellular senescence.

• DIRAS3
• adipocyte
• adipogenesis
• adipose stem cell
• adipose stromal/progenitor cell
• aging
• mTOR
• obesity
• senescence

• E2F4/p107/p130
• Myf5
• MyoD
• Pax7
• Prdm16
• Ucp1
• brown adipocytes
• cell fate control
• muscle progenitor cells

• Adipose Tissue, Beige/metabolism
• Adipose Tissue, Brown/metabolism
• Energy Metabolism
• Feedback, Physiological
• Humans
• Obesity/drug therapy
• Obesity/metabolism

• Adipocytes, Beige/metabolism
• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White/metabolism
• Animals
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Cold Temperature
• DNA-Binding Proteins/genetics
• Diet, High-Fat
• Gene Expression Regulation
• Inhibitor of Differentiation Protein 1/genetics
• Mice
• Mice, Transgenic
• Obesity/genetics
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
• Real-Time Polymerase Chain Reaction
• Thermogenesis/genetics
• Transcription Factors/genetics
• Uncoupling Protein 1/genetics

• DP2 DK105565 NIDDK NIH HHS
• K22 CA168828 NCI NIH HHS
• National Cancer Institute
• National Institute of Diabetes and Digestive and Kidney Diseases

Browning is the process of increasing the number of brite cells, which helps to increase energy expenditure and reduce obesity. Consumption of natural and non-toxic herbal extracts that possess the browning effect is an attractive anti-obesity strategy. In this study, we examined the browning effect of cinnamon extract. We found that cinnamon extract (CE) induced typical brown adipocyte multiocular phenotype in 3T3-L1 adipocytes. The treatment also increased brown adipocytes markers and reduced white adipocytes markers in the 3T3-L1 adipocytes. In ex vivo studies, we found that CE increased brown adipocytes markers in the subcutaneous adipocytes isolated from db/db mice and diet-induced obesity (DIO) mice. However, CE did not significantly affect UCP1 expression in the adipocytes isolated from perinephric adipose tissue and epididymal adipose tissue. β3-adernergic receptor (β3-AR) antagonist reduced the CE-enhanced UCP1 expression, suggesting an involvement of the β3-AR activity. Oral administration of CE significantly increased UCP1 expression in the subcutaneous adipose tissue in vivo and reduced the body weight of the DIO mice. Taken together, our data suggest that CE has a browning effect in subcutaneous adipocytes. Our study suggests a natural non-toxic herbal remedy to reduce obesity.

• Aging and obesity
• p53 and Rb on adipogenesis
• p53 and Rb on obesity

• Brown adipogenesis
• gene regulatory network
• metabolism
• signal transduction

Understanding mechanisms by which a population of beige adipocytes is increased in white adipose tissue (WAT) reflects a potential strategy in the fight against obesity and diabetes. Cyclic adenosine monophosphate (cAMP) is very important in the development of the beige phenotype and activation of its thermogenic program. To study effects of cyclic nucleotides on energy homeostatic mechanisms, mice were generated by targeted inactivation of cyclic nucleotide phosphodiesterase 3b (Pde3b) gene, which encodes PDE3B, an enzyme that catalyzes hydrolysis of cAMP and cGMP and is highly expressed in tissues that regulate energy homeostasis, including adipose tissue, liver, and pancreas. In epididymal white adipose tissue (eWAT) of PDE3B KO mice on a SvJ129 background, cAMP/protein kinase A (PKA) and AMP-activated protein kinase (AMPK) signaling pathways are activated, resulting in “browning” phenotype, with a smaller increases in body weight under high-fat diet, smaller fat deposits, increased β-oxidation of fatty acids (FAO) and oxygen consumption. Results reported here suggest that PDE3B and/or its downstream signaling partners might be important regulators of energy metabolism in adipose tissue, and potential therapeutic targets for treating obesity, diabetes and their associated metabolic disorders.

• Ink4a/Arf
• adipose
• beige adipocytes
• cellular aging
• cold exposure
• mural cells
• senescence
• thermogenesis

• GR
• adipogenesis
• dexamethasone
• glucocorticoid receptor

• E2F1
• cancer metabolism
• cell cycle regulators
• metabolic diseases
• obesity

• Adipocytes
• BMP signaling
• BMSC
• Bone
• Cartilage
• Chondrogenesis
• Klf10
• Osteogenesis
• Osx
• Runx2

• Adipogenesis
• Animals
• Bone Marrow Cells/cytology
• Bone Marrow Cells/metabolism
• Bone Morphogenetic Proteins/metabolism
• Bone Regeneration
• Cell Line
• Chickens
• Chondrogenesis
• Early Growth Response Transcription Factors/metabolism
• HEK293 Cells
• Humans
• Kruppel-Like Transcription Factors/metabolism
• Mesenchymal Stem Cells/cytology
• Mice
• Osteogenesis
• Signal Transduction
• Sp7 Transcription Factor/metabolism
• Stromal Cells/cytology
• Stromal Cells/metabolism