Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Prieur, Xavier; Dollet, Lucile; Takahashi, Mami; Nemani, Mona; Pillot, Bruno; May, Cédric Le; Mounier, Cathérine; Takigawa-Imamura, Hisako; Zélénika, Diana; Matsuda, Fumihiko; Fève, Bruno; Capeau, Jacqueline; Lathrop, Mark; Costet, Philippe; Cariou, Bertrand; Magré, Jocelyne

doi:10.1007/s00125-013-2926-9

Cited by 87 publications

(152 citation statements)

References 38 publications

(54 reference statements)

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“…In support of this hypothesis, Rosi treatment significantly improved a number of metabolic profiles of the ASKO mice and also rescued the adipogenic defect in Seipin 2/2 mouse embryonic fibroblasts, as shown recently (Fig. 7) (8). It should also be noted that AGPAT2 and LPIN1 are key mammalian genes linked to severe generalized lipodystrophy, and genetic ablation of either gene also causes accumulation of PA, which could account for the failure in adipogenesis (32)(33)(34).…”

Section: Seipin and Ppar-gsupporting

confidence: 80%

“…We and others have established an essential role of SEIPIN in adipogenesis both in vitro and in vivo (6)(7)(8)16,17). However, SEIPIN is highly expressed in mature adipocytes, where its function is completely unknown.…”

Section: Discussionmentioning

confidence: 98%

“…The hypertrophy of adipocytes is likely associated with the role of SEIPIN in LD expansion. Although aggregates of small LDs were found in SEIPIN/Fld1-deficient cells (9)(10)(11)27), the most striking change was the formation of giant/supersized LDs (8,10,12). Upregulation of PA, a fusogenic lipid, is believed to contribute to the formation of supersized LDs (21,28), and indeed, PA is increased in ASKO adipose tissue ( Fig.…”

Section: Seipin Adipocyte Hypertrophy and Progressive Lipodystrophymentioning

confidence: 92%

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Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

et al. 2014

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Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of white and brown adipose tissue, insulin resistance, and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species, including ceramides, in ASKO adipose tissue as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific peroxisome proliferator–activated receptor-γ (Pparγ) knockout (FKO-γ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes and reveal an intimate relationship between SEIPIN and PPAR-γ.

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Section: Seipin and Ppar-gsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 98%

Section: Seipin Adipocyte Hypertrophy and Progressive Lipodystrophymentioning

confidence: 92%

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Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

et al. 2014

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“…Cold exposure or ADRB3 agonists activate the classic lipolytic pathway through ARs to stimulate cAMP/protein kinase A (PKA) signaling, lipid mobilization, and browning in WAT ( 30 ). Bscl2-defi cient murine embryonic fi broblasts or stromal vascular cells exhibited increased basal cAMP/PKAmediated lipolysis during differentiation, leading to termination of adipogenesis ( 10,12 ). Conversely, adipose-specifi c SEIPIN knockout (ASKO) mice with FABP4-Cre-mediated Bscl2 deletion exhibited decreased lipolysis in response to ␤ -AR agonists in vivo ( 19 ).…”

Section: Body Composition and Analysis Of Energy Balancementioning

confidence: 99%

“…Incubation medium was added to suspend the adipocytes at 1.5 × 10 5 cells/ml. Equal (1 ml) aliquots of cell suspensions were transferred to 13 ml polystyrene tubes and incubated in KRBH medium supplemented with 2% BSA, 5.5 mM glucose, 300 M palmitic acid and 0.4 Ci/ml [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitic acid (Perkin Elmer Life Sciences). Tubes were then sealed with a rubber stopper which contained hyamine hydroxide-soaked fi lter paper and incubated at 37°C for 2 h while gently shaking every 30 min .…”

Section: Bscl2mentioning

confidence: 99%

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Zhou

Lei

Benson

et al. 2015

Journal of Lipid Research

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BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

Zhou

et al. 2022

Clinical & Translational Med

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Background Heart failure (HF) is one of the leading causes of death worldwide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli‐Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2 −/− mice exhibit hypertrophic cardiomyopathy with reduced cardiac steatosis. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Methods We generated mice with cardiomyocyte‐specific deletion of Bscl2 ( Bscl2 cKO ) and studied their cardiac substrate utilisation, bioenergetics, lipidomics and contractile function under baseline or after either a treatment regimen using fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) or a prevention regimen with high‐fat diet (HFD) feeding. Mice with partial ATGL deletion and cardiac‐specific deletion of Bscl2 were also generated followed by cardiac phenotyping. Results Different from hypertrophic cardiomyopathy in Bscl2 −/− mice, mice with cardiac‐specific deletion of Bscl2 developed systolic dysfunction with dilation. Myocardial BSCL2 deletion led to elevated ATGL expression and FAO along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2 cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, cardiac dysfunction in Bscl2 cKO mice could be partially reversed by FAO inhibitor TMZ, or prevented by genetic abolishment of one ATGL allele or HFD feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2 cKO hearts, which were partially normalised by TMZ or HFD. Conclusions We identified a new form of cardiac dysfunction with excessive lipid utilisation which ultimately causes cardiac substrate depletion and bioenergetics failure. Our findings also uncover a crucial role of BSCL2 in controlling cardiac lipid catabolism and contractile function and provide novel insights into metabolically treating energy‐starved HF using FAO inhibitor or HFD.

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Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Cited by 87 publications

References 38 publications

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

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