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Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic Bscl2 -/- (seipin knockout [SKO]) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice. [ 18 F]Fludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the O -GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the O -GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors., (© 2017 by the American Diabetes Association.)

Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip congenital lipodystrophy (BSCL) linked to seipin deficiency. Bscl2-/- mice displayed a progressive adipose tissue loss with aging as evidenced by the altered profile of residual fat pads and the decrease in adiponectin plasma levels in 12- vs. 4-week-old animals. Aiming to prevent this impairment, we treated 6-week-old Bscl2-/- mice with an FGF21 analog (LY2405319) for a period of 28 days. FGF21 treatment increased adiponectin plasma levels and normalized insulin sensitivity in Bscl2-/- mice by improving the white adipose tissue gene expression pattern. To further decipher the molecular pathways altered by seipin deficiency in mature adipocytes, we developed a unique inducible seipin knockdown cell line (SKD). SKD showed chronic activation of the p38 MAPK pathway associated with apoptotic cell death. Interestingly, FGF21 treatment exerted an antistress effect on SKD cells, reducing p38 MAPK phosphorylation and limiting mature adipocyte loss. Our data demonstrate that FGF21 treatment improves the metabolic profile of Bscl2-/- lipodystrophic mice, partly by improving mature adipocyte maintenance through suppression of cellular stress via inhibition of p38 MAPK activity. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterized by near absence of adipose tissue and severe insulin resistance. Since the discovery of the gene in 2001, several cellular studies intended to unravel the biological function of seipin and revealed that seipin-deficiency alters adipocyte differentiation and lipid droplet morphology. However, the exact function of the protein remains unclear and the pathophysiology of BSCL in patients carrying BSCL2/seipin mutations is poorly understood. A major breakthrough in the field of seipin came recently, with the demonstration by three independent groups that Bscl2-deficient mice (Bscl2 −/−) developed severe lipodystrophy with only residual white and brown fat pads, validating a critical role for seipin in adipose tissue homeostasis. Using in vivo, ex vivo and in vitro methods, these studies demonstrate that seipin plays a key role in adipogenesis, lipid droplet homeostasis and cellular triglyceride lipolysis. In addition to adipose tissue impairment, Bscl2 −/− mice are diabetic and display severe hepatic steatosis. Treatment with thiazolidinediones (TZD) in Bscl2 −/− mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype. Except an unexpected hypotriglyceridemia, Bscl2 −/− mice phenotype represents an almost perfect picture of the human disease. This review analyses how these studies using Bscl2 −/− mice brought new insights into seipin function and the mechanisms involved in the pathophysiology of BSCL. We also analyse some of the human data in the light of the mouse phenotyping and discuss the validity of Bscl2 − / − mice model to test pharmaceutical approaches for treating BSCL and its associated metabolic complications. [Copyright &y& Elsevier]