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Heart failure with preserved ejection fraction (HFpEF) is a growing public health concern, with rising incidence alongside high morbidity and mortality. However, the pathophysiology of HFpEF is not yet fully understood. The association between HFpEF and the metabolic syndrome (MetS) suggests that dysregulated lipid metabolism could drive diastolic dysfunction and subsequent HFpEF. Herein we summarise recent advances regarding the pathogenesis of HFpEF in the context of MetS, with a focus on impaired lipid handling, myocardial lipid accumulation and subsequent lipotoxicity.

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune-tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the metabolic regulation of macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical T helper 2 cell cytokine interleukin-4 to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising reactive oxygen species levels. Reactive oxygen species serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.

SummaryObesity in mice and humans is associated with elevated levels of at least two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. Here we used tissue selective knockout mouse models to establish that, like FGF21, circulating GDF15 is primarily derived from the liver, rather than adipose tissue, muscle or macrophages in high fat fed mice. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in high fat fed mice but is associated with significantly greater hepatic steatosis and insulin resistance. Collectively the data suggest that activation of the integrated stress response in hepatocytes is a major driver for GDF15 and FGF21 secretion in the context of overfeeding, and that they both act to alleviate this metabolic stress.

Objective Neuroimmune interactions between the sympathetic nervous system (SNS) and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue. It has been proposed that the SNS maintains adipose tissue macrophages (ATMs) in an anti-inflammatory state via direct norepinephrine (NE) signaling to macrophages. This study aimed to investigate the physiological importance of this paradigm by utilizing a mouse model in which the adrenergic signaling from the SNS to macrophages, but not to other adipose tissue cells, was disrupted. Methods We generated a macrophage-specific B2AR knockout mouse (Adrb2ΔLyz2) by crossing Adrb2fl/fl and Lyz2Cre/+ mice. We have previously shown that macrophages isolated from Adrb2ΔLyz2 animals do not respond to NE stimulation in vitro. Herein we performed a metabolic phenotyping of Adrb2ΔLyz2 mice on either chow or high-fat diet (HFD). We also assessed the adipose tissue function of Adrb2ΔLyz2 animals during fasting and cold exposure. Finally, we transplanted Adrb2ΔLyz2 bone marrow to low-density lipoprotein receptor (LDLR) knockout mice and investigated the development of atherosclerosis during Western diet feeding. Results We demonstrated that SNS-associated ATMs have a transcriptional profile indicative of activated beta-2 adrenergic receptor (B2AR), the main adrenergic receptor isoform in myeloid cells. However, Adrb2ΔLyz2 mice have unaltered energy balance on a chow or HFD. Furthermore, Adrb2ΔLyz2 mice show similar levels of adipose tissue inflammation and function during feeding, fasting, or cold exposure, and develop insulin resistance during HFD at the same rate as controls. Finally, macrophage-specific B2AR deletion does not affect the development of atherosclerosis on an LDL receptor-null genetic background. Conclusions Overall, our data suggest that the SNS does not directly modulate the phenotype of adipose tissue macrophages in either lean mice or mouse models of cardiometabolic disease. Instead, sympathetic nerve activity exerts an indirect effect on adipose tissue macrophages through the modulation of adipocyte function., Graphical abstract Image 1, Highlights • Sympathetic nerve-associated macrophages in white adipose tissues exhibit a transcriptional signature of B2AR activation. • Macrophage-specific B2AR knockout does not affect the phenotype of adipose tissue macrophages. • Macrophage B2AR signaling does not affect adipose tissue function during fasting or cold exposure. • Macrophage B2AR is dispensable for the development of insulin resistance and atherosclerosis in obesity.

Contains fulltext : 232477.pdf (Publisher’s version ) (Open Access) Tissue-resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti-inflammatory and tissue-reparative phenotype in macrophages. As NE has a well-established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow-derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2-adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride-laden macrophages. We demonstrate that these responses are mediated by a B2AR activation-dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.

Hutchinson&ndash, Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients&rsquo, endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin&ndash, zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases.

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation

International audience; Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including musculardystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shownto alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within thenucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophicfeatures, combining generalized or partial fat atrophy and metabolic alterations associated withinsulin resistance, could result from altered adipocyte differentiation or from altered fat structure.Recent studies shed some light on how pathogenic A-type lamin variants could triggerlipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations inadipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility.Premature senescence of vascular cells could contribute to cardiovascular complications. Inaffected families, metabolic alterations occur at an earlier age across generations, which couldresult from epigenetic deregulation induced by LMNA mutations. Novel cellular modelsrecapitulating adipogenic developmental pathways provide scalable tools for disease modelingand therapeutic screening.

Objective Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and results Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Conclusions Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH., Highlights • Human NASH biopsies’ transcriptomics analysis features metabolic pathway rewiring. • SCAP/SREBP/INSIG1 modulation promotes lipid/cholesterol synthesis/remodelling in NASH. • Loss of Insig1 promotes lipid remodelling, preventing hepatic lipotoxicity in NASH. • Loss of Insig1 improves liver damage and wound healing and restrains NASH progression.

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs., eLife digest Although inflammation can be good for the body and help fight off infection, in certain cases it can also be harmful. When immune cells switch on at the wrong time, they can cause damage to cells and tissues. Fat tissue has its own population of immune cells called adipose tissue macrophages that remove dead fat cells and keep the tissue working. However, obesity changes the behaviour of these macrophages so they switch on as though they were fighting an infection and make the fat tissue inflamed. The signals produced by these activated macrophages stop fat tissue working, and this can lead to type 2 diabetes. The trigger that activates macrophages in obesity is not yet clear, but some evidence suggests that it is due to the type of fat available. Fats come in two main forms: saturated, which can lead to high cholesterol, or unsaturated which can reduce the risk of high blood pressure. An increase in saturated fats can cause cells, including macrophages, to become stressed. Researchers showed in 2011 that macrophages in the fatty tissue of obese mice accumulate fat and become inflamed, but it was unclear which types of fat, if any, were driving the inflammation. Now, Petkevicius et al. – including some of the researchers involved in the 2011 work – report that macrophages in the fatty tissue of obese mice make excess phosphatidylcholine, a fat normally found in the cell membrane. Phosphatidylcholine is a type of fat known as a phospholipid and it is made up of two subunits called fatty acids that can either be saturated or unsaturated. In obese people and mice, fatty tissue produces too much of the enzyme that makes phosphatidylcholine, called CCTa. Petkevicius et al. showed that partially removing the CCTa gene from macrophages reduces inflammation, but, unexpectedly, the amount of phosphatidylcholine in the cells stays the same. This is because macrophages respond to the halt in phosphatidylcholine production by removing less of the phospholipid from the membrane. This gives the macrophages time to exchange the saturated fatty acids in phosphatidylcholine for unsaturated fatty acids. Therefore, the longer phosphatidylcholine stays in the membrane, the more likely it is to contain unsaturated fatty acids. Further experiments demonstrated that this change counteracts the effects caused by excess saturated fats, protecting the cells and reducing inflammation. Although the understanding of obesity is still in its early stages, this study adds another piece of the puzzle. If we can understand why fat stops working in obesity, and how this leads to disease, it could aid the design of new treatments for type 2 diabetes.

Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.

White adipose tissue (WAT) inflammation causes insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and systemic insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Unlike previously suggested, this was not due to lower palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis and pro-inflammatory activation of ATMs.

Several alterations in nuclear envelope proteins building up the lamina meshwork beneath the inner nuclear membrane (mutations in lamins A/C, alterations of prelamin-A maturation, lamin B mutations or deregulation) have been shown to be responsible for or associated to human lipodystrophic syndromes. Lipodystrophic syndromes are rare and heterogeneous diseases, either genetic or acquired, characterized by generalized or partial fat atrophy associated with metabolic complications comprising insulin-resistant diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Recent advances in the molecular genetics of different types of lipodystrophies generally pointed to primary adipocyte alterations leading to impaired adipogenesis and/or deregulation of the adipocyte lipid droplet. However, the precise mechanisms linking nuclear envelope abnormalities to lipodystrophies remain largely unknown. The phenotype of nuclear envelope-linked lipodystrophies ranges from the typical familial partial lipodystrophy of the Dunnigan type (FPLD2), due to heterozygous substitutions of the 482nd arginine of lamins A/C, to complex diseases that can combine lipodystrophy, metabolic complications, muscular or cardiac alterations and/or signs of accelerated aging. In this review we present the clinical, tissular and cellular characteristics of the nuclear envelope-linked lipodystrophies, as well as their hypothetical pathophysiological mechanisms.

Mutations in the LMNA gene, encoding the nuclear intermediate filaments the A-type lamins, result in a wide variety of diseases known as laminopathies. Some of them, such as familial partial lipodystrophy of Dunnigan and metabolic laminopathies, are characterized by lipodystrophic syndromes with altered fat distribution and severe metabolic alterations with insulin resistance and dyslipidaemia. Metabolic disturbances could be due either to the inability of adipose tissue to adequately store triacylglycerols or to other cellular alterations linked to A-type lamin mutations. Indeed, abnormal prelamin A accumulation and farnesylation, which are clearly involved in laminopathic premature aging syndromes, could play important roles in lipodystrophies. In addition, gene expression alterations, and signalling abnormalities affecting SREBP1 (sterol-regulatory-element-binding protein 1) and MAPK (mitogen-activated protein kinase) pathways, could participate in the pathophysiological mechanisms leading to LMNA (lamin A/C)-linked metabolic alterations and lipodystrophies. In the present review, we describe the clinical phenotype of LMNA-linked lipodystrophies and discuss the current physiological and biochemical hypotheses regarding the pathophysiology of these diseases.

Les lipodystrophies d’origine genetique sont des entites rares. Il s’agit d’un groupe de maladies monogeniques, pour lesquelles plusieurs genes differents ont ete mis en cause. Cliniquement, les syndromes lipodystrophiques associent insulino-resistance, troubles du developpement ou de la repartition du tissu adipeux et dyslipidemies majeures. Les lipodystrophies sont classees selon le caractere generalise ou partiel de la lipoatrophie : – Le syndrome de Berardinelli-Seip ou lipoatrophie congenitale generalisee Il est le plus souvent lie a aux mutations de la seipine, ou d’AGPAT2 , enzyme de la voie de synthese des triglycerides adipocytaires. Plus rarement, des mutations de la caveoline 1 ou de la cavine 1, qui appartiennent a des invaginations membranaires appelees caveolae, et qui sont des proteines structurales de la gouttelette lipidique adipocytaire un role dans la formation de la gouttelette lipidique adipocytaire, ont ete rapportees dans des syndromes de Berardinelli-Seip. – Le syndrome de Dunnigan ou lipodystrophie partielle familiale. Il est lie le plus souvent aux mutations du gene de la lamine A/C, proteine ubiquitaire du reseau filamentaire de la lamina, situe sous la membrane interne du noyau cellulaire, ou du gene du PPARg, facteur transcriptionnel adipogenique. Des mutations dans d’autres genes rendent compte d’autres cas, plus rares; il s’agit des genes codant pour AkT2 (intermediaire de la voie de signalisation insulinique), CIDEC (proteine de la gouttelette lipidique adipocytaire), ou la perilipine, qui structure la gouttelette et regule la lipolyse adipocytaire, et dont l’implication dans certaines lipodystrophies partielles autosomales dominantes vient d’etre montree. – D’autres mutations de la lamine A/C donnent des syndromes d’insulino-resistance avec lipodystrophie atypique, parfois minime (laminopathies metaboliques) et des syndromes de lipodystrophies partielles ou generalisees dans le cadre de syndromes de vieillissement acceleres (dysplasie acromandibulaire, progeria), pouvant aussi etre lies a des mutations d’une l’enzyme de maturation de la prelamine A en lamine A, ZMPSTE24. – D’autres syndromes lipodystrophiques familiaux, generalises ou partiels, restent de cause inconnue : le role d’autres genes reste a decouvrir. L’identification des phenotypes et des genotypes de ces pathologies est encore incomplete mais ces maladies, diverses, genetiquement determinees, sont des modeles pour l’etude du determinisme plus general de la resistance a l’insuline. Le traitement est identique au traitement des autres situations d’insulino-resistance : exercice physique, insulino-sensibilisateurs, insuline. Il doit egalement rendre en charge l’ensemble des facteurs de risque cardio-vasculaires. Des essais cliniques de traitement par la leptine sont encourageants.

cope Consumption of products rich in flavan-3-ols, such as tea and cocoa, has been associated with decreased obesity, partially dependent on their capacity to enhance energy expenditure. Despite these phenolics having been reported to increase the thermogenic program in brown and white adipose tissue, flavan-3-ols are vastly metabolised in vivo to phenyl-γ-valerolactones. Therefore, we hypothesize that phenyl-γ-valerolactones may directly stimulate the differentiation and the activation of brown adipocytes. Methods and results Immortalized brown pre-adipocytes were differentiated in presence of (R)-5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (VL1), (R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulphate (VL2), (R)-5-phenyl-γ-valerolactone-3′,4′-di-O-sulphate (VL3), at concentrations of 2 or 10μM, whereas fully differentiated brown adipocyte were treated acutely (6-24h). None of the treatments regulated the expression levels of the uncouple protein 1, nor of the main transcription factors involved in brown adipogenesis. Similarly, mitochondrial content was unchanged after treatments. Moreover these compounds did not display peroxisome proliferator-activated receptor γ-agonist activity, as evaluated by luciferase assay, and did not enhance norepinephrine-stimulated lipolysis in mature adipocytes. However, both VL1 and VL2 prevented oxidative stress caused by H2O2. Conclusion Phenyl-γ-valerolactones and their sulphated forms do not influence brown adipocyte development or function at physiological or supraphysiological doses in vitro, but they are active protecting brown adipocytes from increased reactive oxygen species production. This article is protected by copyright. All rights reserved

Genetic lipodystrophic syndromes are rare diseases characterized by generalized or partial fat atrophy (lipoatrophy) associated with severe metabolic complications such as insulin resistance (IR), diabetes, dyslipidemia, nonalcoholic fatty liver disease, and ovarian hyperandrogenism. During the last 15 years, mutations in several genes have been shown to be responsible for monogenic forms of lipodystrophic syndromes, of autosomal dominant or recessive transmission. Although the molecular basis of lipodystrophies is heterogeneous, most mutated genes lead to impaired adipogenesis, adipocyte lipid storage, and/or formation or maintenance of the adipocyte lipid droplet (LD), showing that primary alterations of adipose tissue (AT) can result in severe systemic metabolic and endocrine consequences. The reduced expandability of AT alters its ability to buffer excess caloric intake, leading to ectopic lipid storage that impairs insulin signaling and other cellular functions (“lipotoxicity”). Genetic studies have also pointed out the close relationships between ageing, inflammatory processes, lipodystrophy, and IR.

Objective— Some mutations in LMNA , encoding A-type lamins, are responsible for Dunnigan-type-familial partial lipodystrophy (FPLD2), with altered fat distribution and metabolism. The high prevalence of early and severe cardiovascular outcomes in these patients suggests that, in addition to metabolic risk factors, FPLD2-associated LMNA mutations could have a direct role on the vascular wall cells. Approach and Results— We analyzed the cardiovascular phenotype of 19 FPLD2 patients aged >30 years with LMNA p.R482 heterozygous substitutions, and the effects of p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. In 68% of FPLD2 patients, early atherosclerosis was attested by clinical cardiovascular events, occurring before the age of 45 in most cases. In transduced endothelial cells, exogenous wild-type-prelamin-A was correctly processed and localized, whereas p.R482W-prelamin-A accumulated abnormally at the nuclear envelope. Patients’ fibroblasts also showed a predominant nuclear envelope distribution with a decreased rate of prelamin-A maturation. Only p.R482W-prelamin-A induced endothelial dysfunction, with decreased production of NO, increased endothelial adhesion of peripheral blood mononuclear cells, and cellular senescence. p.R482W-prelamin-A also induced oxidative stress, DNA damages, and inflammation. These alterations were prevented by treatment of endothelial cells with pravastatin, which inhibits prelamin-A farnesylation, or with antioxidants. In addition, pravastatin allowed the correct relocalization of p.R482W-prelamin-A within the endothelial cell nucleus. These data suggest that farnesylated p.R482W-prelamin-A accumulation at the nuclear envelope is a toxic event, leading to cellular oxidative stress and endothelial dysfunction. Conclusions— LMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients’ early atherosclerosis.

Human genetic lipodystrophic syndromes are rare conditions with total or partial body fat loss, severe lipid and glucose alterations and insulin resistance, leading to early diabetes, cardiovascular and hepatic complications. Most generalised forms, recessively inherited, result from mutations in four proteins, mainly 1-acylglycerol-3-phosphate-O-acyltransferase-2 (AGPAT2) involved in triglyceride synthesis, or seipin involved in the adipocyte lipid droplet formation/maintenance but also in caveolin-1 and cavin-1/polymerase I and transcript release factor, expressed in caveolae and at the lipid droplet surface. Partial lipodystrophic syndromes, generally dominantly inherited, mainly involve A-type lamins (LMNA), forming the nuclear lamina, or the adipogenic transcription factor peroxisome proliferator-activated-receptor-gamma. Less frequently Akt2, in the insulin signalling pathway, perilipin and cell-death-inducing-DFF45-like-effector-C, controlling adipocyte triglyceride storage, are affected. Insulin resistance and lipodystrophy can also be present in genetic syndromes of premature ageing as the Hutchinson–Gilford progeria or mandibuloacral dysplasia (LMNA or ZMPSTE24) and the Werner syndrome (affecting the helicase WRN). Patients’ management is difficult and recombinant human leptin treatment could be helpful. Key Concepts: Adipose tissue releases a number of factors and hormones and plays an important physiological role, only recently considered. Genetic lipodystrophic syndromes are a heterogeneous group of diseases with lipoatrophy either generalised or partial. The very limited fat expansion seen in lipodystrophies results in severe metabolic alterations and early complications as a result of fat overwhelming by nutriments. Partial lipodystrophies due to a single gene mutation associate both fat hypertrophy and fat atrophy, stressing for the differential physiology of differently located fat depots. A number of genetic lipodystrophies affect proteins involved in lipid droplet function, which stresses the underrecognised role of lipid droplet in adipocyte physiology. The transcription factor PPARγ plays important roles in adipogenesis but also at the level of the vascular wall. Mutations in the gene encoding lamin A/C result in a wide range of diseases collectively called laminopathies. Human recombinant leptin can improve the metabolic alterations present in lipodystrophic patients with a low leptin level. Keywords: adipose tissue; lipid droplets; adipogenesis; insulin resistance; diabetes; dyslipidaemia; metabolic complications