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Aims/hypothesis Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods Bscl2−/− mice were generated and phenotyped. X. Prieur, L. Dollet and M. Takahashi contributed equally to this study.Electronic supplementary material The online version of this article

Obesity is an important aspect of the metabolic syndrome and is often associated with chronic inflammation. In this context, inflammation of organs participating in energy homeostasis (such as liver, adipose tissue, muscle and pancreas) leads to the recruitment and activation of macrophages, which secrete pro-inflammatory cytokines. Interleukin-1β secretion, sustained C-reactive protein plasma levels and activation of the NLRP3 inflammasome characterize this inflammation. The Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. This enzyme catalyzes the generation of monounsaturated fatty acids (MUFAs)—major components of triglycerides stored in lipid droplets—from saturated fatty acid (SFA) substrates. In this review, we describe the molecular effects of specific classes of fatty acids (saturated and unsaturated) to better understand the impact of different diets (Western versus Mediterranean) on inflammation in a metabolic context. Given the beneficial effects of a MUFA-rich Mediterranean diet, we also present the most recent data on the role of SCD1 activity in the modulation of SFA-induced chronic inflammation.

Obesity and associated metabolic complications, such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), are in constant increase around the world. While most obese patients show several metabolic and biometric abnormalities and comorbidities, a subgroup of patients representing 3% to 57% of obese adults, depending on the diagnosis criteria, remains metabolically healthy. Among many other factors, the gut microbiota is now identified as a determining factor in the pathogenesis of metabolically unhealthy obese (MUHO) individuals and in obesity-related diseases such as endotoxemia, intestinal and systemic inflammation, as well as insulin resistance. Interestingly, recent studies suggest that an optimal healthy-like gut microbiota structure may contribute to the metabolically healthy obese (MHO) phenotype. Here, we describe how dietary medium chain triglycerides (MCT), previously found to promote lipid catabolism, energy expenditure and weight loss, can ameliorate metabolic health via their capacity to improve both intestinal ecosystem and permeability. MCT-enriched diets could therefore be used to manage metabolic diseases through modification of gut microbiota.

Abstract. In normal tissues, energy-providing lipids come principally from circulating lipids. However, in growing tumors, energy supply is mainly provided by lipids coming from de novo synthesis. It is not surprising to see elevated expression of several lipogenic genes in tumors from different origins. The role of lipogenic genes in the establishment of the primary tumor has been clearly established. A large number of studies demonstrate a role of fatty acid synthase in the activation of cell cycle and inhibition of apoptosis in tumor cells. Other lipogenic genes such as the acetyl CoA carboxylase (ACC) and the stearoyl CoA desaturase 1 (SCD1) are highly expressed in primary tumors and also appear to play a role in their development. However, the role of lipogenesis in the metastatic process is less clear. In the present review, we aim to present the most recent evidences for the key role of lipogenic enzymes in the metastatic process and in epithelial to mesenchymal transition.

Apolipoprotein D (apoD), a widely expressed lipocalin, has the capacity to transport small hydrophobic molecules. Although it has been proposed that apoD may have multiple tissue-specific, physiological ligands and functions, these have yet to be identified. To gain insight in some of its functions, we generated transgenic mice overexpressing human apoD (H-apoD) under the control of neuron-specific promoters. In Thy-1/apoD and NSE/apoD mice, expression of H-apoD was strong in the nervous system although weakly detected in peripheral organs such as the liver and blood cells. These mice displayed not entirely anticipated metabolic defects. Although they are not obese and have normal lipid concentration in circulation, Thy-1/apoD and NSE/apoD mice are glucose intolerant, insulin resistant, and develop hepatic steatosis. The steatosis and its associated insulin resistance are correlated with impairments in hepatic lipogenesis. However, they are not strongly related with inflammation. This impaired insulin response is not caused by a decrease in circulating leptin or a modulation of adiponectin and resistin levels. These results suggest that variations in the levels and/or sites of apoD expression influence the lipid and glucose metabolism, consolidating apoD as a target for insulin-resistance-related disorders.

The stearoyl-CoA desaturase 1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids. This enzyme is a critical control point regulating hepatic lipogenesis and lipid oxidation. Therefore SCD1 may be a potential therapeutic target in the treatment of obesity and metabolic syndrome. Regulation of SCD1 expression occurs primarily at the level of transcription. In the present study, we characterized the insulin response elements (IREs) and the insulin signaling pathway mediating the regulation of SCD1 gene transcription in liver. In chicken embryo hepatocytes (CEH) and HepG2 cells, insulin stimulates SCD1 promoter activity by 2.5 folds. This activation is mediated by two different IREs on the chicken promoter, one localized between −1,975 and −1,610 bp and one between −372 and −297 bp. The latter binds both NF-Y and SREBP-1 transcription factors in response to insulin. We also demonstrated that insulin induction of SCD1 gene expression and promoter activity is abolished by pre-incubation of cells with specific inhibitors of both PI3-kinase (LY294002) and mTor (Rapamycin) or by over-expression of a dominant negative mutant of PI3-kinase. The PI3-kinase and mTor pathway mediates the insulin response on both IREs. In summary, insulin activates SCD1 gene expression in liver via a signaling pathway that involves PI3-kinase and mTor and the downstream transcription factors NF-Y and SREBP-1.Sentence summary: Insulin regulates SCD1 gene expression via two different IREs. The most 3′ IRE is localized between −372 and −297 bp and binds the NF-Y and SREBP-1 transcription factors in response to insulin. PI3-kinase and mTor mediate the action of insulin on both IREs.

Maternal hypercholesterolemia (HC) during pregnancy and gestational diabetes mellitus (GDM) are associated with disturbance of fetal development which may also modify key features of placental functions. In this study, we evaluated the impact of maternal hypercholesterolemia on placental cholesterol and lipid metabolism in 59 women classified in two groups according to the median concentration of plasma total cholesterol (6.42 mM). The impact of GDM was also evaluated on the metabolism of placentas obtained from 7 insulin-treated GDM and 7 non-GDM women. We showed that high maternal circulating cholesterol is associated with a significant increase in the LDL-cholesterol, ApoB-100 and triglyceride concentrations in the maternal blood. However the level of cholesterol in the venous cord blood and placenta remains unchanged in response to modification in maternal cholesterol profile. The levels of Fatty acid synthase (FAS) and SREBP-2 expressions in placenta are significantly increased in the HC group while expression of both sterol regulatory element-binding proteins-1 (SREBP-1) and HMG-CoA reductase (HMGR) are not modified. GDM is not associated with modification in the maternal lipid profile but it increases the concentration of inflammatory cytokines (IL-1beta and TNF-alpha) in placenta which correlates with a dramatic induction of FAS expression without affecting the expression of mature SREBPs proteins. In conclusion, our study suggests that in placenta, expressions of key proteins involved in de novo lipid synthesis are affected by changes in maternal metabolism (HC and GDM) that may subsequently affect fetal development.