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International audience; BACKGROUND: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes.REVIEW: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males.CONCLUSIONS: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications

Background Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. Objective To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. Methods We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. Results Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. Conclusion MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

Le tissu adipeux est reconnu en tant « qu’organe » capable de synthetiser et de secreter plusieurs centaines de molecules qui exercent des actions pleiotropes, en particulier sur la regulation du metabolisme glucidolipidique, l’inflammation, l’angiogenese ou la reproduction, molecules rassemblees sous le terme d’adipokines. De nombreux travaux ont ete realises sur les adipokines « phares » que sont la leptine et l’adiponectine, notamment en raison de leur implication dans le metabolisme energetique. Cependant, de nombreuses adipokines ont emerge depuis et representent des cibles prometteuses, en particulier dans le contexte des desordres metaboliques associes a l’obesite. Dans cet article, nous ferons un point non exhaustif des adipokines « classiques » ou plus recemment decouvertes dans le domaine de l’obesite et des maladies metaboliques.

Type 1 diabetes accounts for 5 to 10% of all diabetes cases. It appears most often during childhood or adolescence. We report the case of a hypertensive overweight patient of 79 years who consulted for asthenia in context of polyuria-polydipsia syndrome in which blood glucose assay revealed a diabetes mellitus associated with ketosis. Despite the age, the body mass index and the history of the patient, type 1 diabetes diagnosis should be considered in this clinical presentation with brutal and symptomatic early. The imagery excluding a pancreatic tumor and positive research of circulating autoantibodies will confirm the diagnosis.

Introduction Les syndromes lipodystrophiques sont des maladies rares caracterisees par un deficit en tissu adipeux et par des troubles metaboliques associant insulino-resistance, dyslipidemie et steatose hepatique, avec un retentissement ovarien chez les femmes. Ils regroupent de nombreuses formes cliniques, la lipoatrophie etant generalisee ou partielle, d’origine genetique ou acquise, revelee a l’âge pediatrique ou chez l’adulte, et accompagnee ou non d’autres co-morbidites, en particulier cardio-vasculaires. Les syndromes lipodystrophiques sont probablement largement sous-diagnostiques. Observations L’atelier « Syndromes lipodystrophiques : diagnostic et prise en charge » nous permettra, sur un mode interactif, d’echanger autour de cas cliniques illustrant les problematiques diagnostiques et therapeutiques, en pratique clinique, des differentes formes de ces maladies. Un examen clinique soigneux, ainsi que des analyses moleculaires ciblees sont importants pour obtenir un diagnostic etiologique et adapter la prise en charge. Nous discuterons aussi des grandes lignes du Protocole National de Diagnostic et de Soins (PNDS) « Syndrome de Dunnigan » lors de cet atelier. Discussion Le centre de reference des Pathologies Rares de l’Insulino-Secretion et de l’insulino-Sensibilite (PRISIS) permet de faciliter le partage des connaissances sur ces syndromes et d’aider a la prise en charge des patients, en particulier grâce a l’organisation de Reunions de Concertation Pluridisciplinaires nationales. La nouvelle pre-indication « diabetes rares de l’enfant et diabetes lipoatrophiques » du Plan France Medecine Genomique 2025 donne a PRISIS la possibilite d’acceder a un nouvel outil diagnostique puissant, le sequencage genomique tres haut debit, qui devrait ameliorer le parcours de soins des patients.

Contexte PPARγ est un recepteur nucleaire essentiel a la differenciation adipocytaire et au developpement trophoblastique. Certains variants de PPARG sont responsables du syndrome lipodystrophique familial partiel-type 3 (FPLD3) avec anomalies adipocytaires et insulino-resistance. Ces variants pourraient aussi affecter le developpement in utero, comme le suggere le cas d’une patiente dont la grossesse s’est compliquee de mort neonatale dans un contexte de prematurite et d’anomalies placentaires vasculaires associees a un variant PPARG-FPLD3. Objectif Etudier le phenotype metabolique et le developpement foetal des patients porteurs de variants pathogenes de PPARG. Patients et methodes Etudes transversale et retrospective de patients avec un variant pathogene PPARG-FPLD3. Resultats 22 patients issus de 13 familles ont ete etudies. L’âge median au diagnostic etait de 36 ans. A l’inclusion, 90 % des patients de plus de 15 ans presentaient un diabete (n = 19/21), 58 % une HTA (n = 12/21), 80 % une hypertriglyceridemie (n = 17/21), 76 % une steatose hepatique (n = 16/21), avec une obesite ou un surpoids dans 62 % des cas (n = 13/21). L’âge moyen au diagnostic de diabete et d’HTA de 22 et 28 ans respectivement. Neuf patients (9/16, 56 %) etaient nes prematures et 50 % (n = 7/14) avaient un retard de croissance intra-uterin (RCIU). Tous les patients dont le variant PPARG etait herite du pere (i.e placenta porteur du variant, mere indemne de FPLD3), presentaient une prematurite et un RCIU. Conclusion Ces resultats suggerent que les variants pathogenes de PPARG responsables de FPLD3 pourraient induire des anomalies placentaires specifiques. Des etudes in vitro sont en cours pour en etudier les mecanismes.

Le syndrome de Turner (ST) est caracterise par une perte complete ou partielle du chromosome X, diagnostique sur le caryotype lymphocytaire. Dans 50 % des cas, il existe une mosaique 45,X/46,XX. Le but de notre etude est de comparer les resultats du frottis buccal associe a une technique d’hybridation in situ par fluorescence (FISH) avec le caryotype lymphocytaire. Une etude prospective, de juillet 2017 a aout 2019, a recrute au sein d’un centre de maladies rares, 142 patientes adultes avec un ST. Un frottis buccal a ete realise, apres un consentement eclaire. Les donnees cliniques ont ete extraites de la base CEMARA. Le pourcentage de cellules 45,X etait identique entre les deux techniques chez seulement 32,4 % des patientes. La difference etait superieure a 41 % pour 12 % de la cohorte. Le pourcentage de cellules 45,X etait plus eleve dans le frottis jugal chez 53 (30,3 %) des patientes. Chez 17 (12 %) patientes, le frottis a modifie le type de l’anomalie genetique du ST, obtenu par le caryotype sanguin. Il a permis d’identifier la presence d’un chromosome Y non detecte sur les lymphocytes (n = 1) et des mosaiques chez des patientes avec une formule 45,X homogene sur les lymphocytes (n = 16). L’amenorrhee secondaire etait plus precoce lorsque le pourcentage de 45,X etait eleve sur le frottis. Le caryotype sanguin reste l’examen de reference pour le diagnostic de ST. Cependant, la FISH sur frottis buccal, technique non invasive, permet d’evaluer plus precisement la constitution chromosomique des patientes avec un ST et ainsi d’optimiser leur prise en charge.

A 67-year-old woman was referred for staging of an insulinoma. CT has shown a pancreatic tumor, a portal thrombus, and an ovarian mass presumed not to be related with the insulinoma. These three lesions were highly positive on Ga DOTATOC PET/CT, leading to the hypothesis of a malignant insulinoma with neoplastic vein thrombus and ovarian metastasis, which was subsequently confirmed histologically. Despite severe hypoglycemia preventing fasting, F-FDG PET/CT was informative, showing significant uptake by the thrombus, which corresponded to the most aggressive lesion (Ki67 of 3.5% for the primary pancreatic tumor and 19.6% for the thrombus).

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since mercredi 28 septembre 2016

International audience; Haemochromatosis represents a common autosomal-recessive hereditary disease that induces iron overload [1]. The most frequent mutation results in a change of cysteine to tyrosine at position 282 (C282Y) in the HFE protein. HFE is required for stimulation of hepcidin, which acts as a regulator of iron intestinal absorption. When mutated, hepcidin is decreased while iron absorption remains inappropriately high, even when iron body stores are replete [2] Haem iron is found in red meat, specifically in haemoprotein. After ingestion, iron is released from haem secondary to lowering of stomach pH and its enzymes. Most of the iron absorption happens in the duodenum and proximal jejunum.

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.

Introduction L’atteinte hypothalamo-hypophysaire (HH) au cours de la sarcoidose est rare et peu decrite. Elle peut entrainer des insuffisances antehypophysaires, une hyperprolactinemie de deconnexion et un diabete insipide. Patients et methodes Etude descriptive multicentrique retrospective sur 32 patients avec sarcoidose HH. Resultats Trente-deux patients (18 femmes) ont ete inclus. Les principaux signes cliniques endocriniens etaient : asthenie (n = 19), amenorrhee (n = 12), dysfonction erectile (n = 10). Trente et un patients avaient des anomalies antehypophysaires : deficit gonadotrope (n = 25), thyreotrope (n = 20), somatotrope (n = 11), corticotrope (n = 2), hyperprolactinemie (n = 24). Quinze avaient un diabete insipide. Un syndrome hypothalamique caracterise par une prise de poids massive (mediane 22 kg) etait retrouve chez 6 patients. L’IRM etait anormale chez 31 patients : tige epaissie (n = 20), infiltration de l’hypothalamus (n = 17), anomalies hypophysaires (n = 11). Tous avaient une sarcoidose multisystemique, dont 26 confirmes par histologie. Parmi les patients recontroles apres traitement de la sarcoidose : 11 avaient une prolactine normalisee (58 %) et 8 avaient recupere une fonction gonadotrope (42 %). Aucune guerison de diabete insipide n’a ete rapportee. Discussion Les deficits gonadotrope, thyreotrope et l’hyperprolactinemie sont les atteintes les plus frequentes dans notre etude realisee sur la plus grande cohorte de sarcoidose HH publiee. Une recuperation de la fonction gonadotrope est observee dans 42 % des cas apres traitement, et une normalisation de la prolatine dans 58 %. La moitie des patients presente un diabete insipide definitif.

Adipose tissue (AT) is now well recognized as an endocrine organ involved in energy homeostasis regulation acting both on the central nervous system and at the local level via its hormonal secretion such as leptin. Recently, the abdominal subcutaneous AT, which is easily accessible by using several procedures, became one of the important parameters used to phenotype morbidly obese patients. Indeed, morphologic and functional modifications such as, adipocyte hypertrophia, inflammation and fibrosis are associated with obesity-related metabolic complications. The objectives of this article are to present the various techniques of abdominal subcutaneous AT biopsies, as well as further information which they can bring. The less morbid technique is the subcutaneous AT needle aspiration, which is currently used in several indications including morbidly obese patient phenotyping. However, it does not allow a complete histological study because it generally provides unstructured AT samples. Surgical AT biopsy, which requires a cutaneous section, is more invasive than the needle aspiration. However, it allows a good quality complete histological study, but with a lesser AT amount than the needle aspiration.

SummaryContext Glucocorticoid therapy may result in adipose tissue redistribution of unknown pathophysiology. Objectives To evaluate the effects of glucocorticoids on adipokine levels and adipose tissue inflammation. To compare the results in patients with or without glucocorticoid-induced lipodystrophy (GIL) after 3 months of therapy. Design and setting Prospective monocentric study. Patients Adult patients initiating systemic, high-dose prednisone therapy for at least 3 months. Blood samples and subcutaneous abdominal adipose tissue biopsies were collected at baseline and month 3. The presence of GIL after 3 months of therapy was assessed using standardized photography. Results Thirty-two patients were enrolled. Blood samples and subcutaneous abdominal adipose tissue were available at baseline and month 3 for 30 patients [median age: 61 (38–79) years, 77% women]. Among those 30 patients, 15 were classified as GIL+ and 15 were GIL− at month 3. Between baseline and month 3, adiponectin and leptin levels increased in the overall population while the level of resistin remained unchanged. At baseline, leptin level was higher [19·3 (8·3–31·1) vs 4·5 (2·4–11·3) μg/l, P = 0·006] and resistin level lower [7·1 (6·3–12·4) vs 10·4 (8·0–21·7) μg/l, P = 0·05] in GIL+ than in GIL− patients. Baseline leptin level was predictive of GIL occurrence. Receiver operating characteristic curve analysis demonstrated that the best diagnostic accuracy was obtained with a baseline leptin cut-off of 5·9 μg/l (sensitivity: 93%, specificity: 60%). At month 3, leptin and adiponectin levels increased more in the GIL+ than in the GIL− group, as did the number of anti-inflammatory M2 macrophages in subcutaneous abdominal fat. Conclusion Glucocorticoid-induced lipodystrophy is associated with a different adipokine profile both before and after glucocorticoid therapy. Serum leptin level prior to glucocorticoid therapy is highly predictive of GIL occurrence.

1. Name of the disease (synonyms): There are four subclasses of Congenital Generalized Lipodystrophy (CGL), also named Berardinelli–Seip Congenital Lipodystrophy (BSCL): Type 1 CGL (CGL1). Type 2 CGL (CGL2). Type 3 CGL (CGL3). Type 4 CGL (CGL4). 2. OMIM# of the disease: CGL1: #608594. CGL2: #269700. CGL3: #612526. CGL4: #613327. 3. Name of the analysed genes or dna/chromosome segments: CGL1: AGPAT2. CGL2: BSCL2. CGL3: CAV1. CGL4: PTRF. 4. OMIM# of the gene(s): AGPAT2: *603100. BSCL2: *606158. CAV1: *601047. PTRF: *603198. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the four gene(s) in ⊠ diagnostic, □ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

To describe the bone imaging features of lipodystrophies in the largest cohort ever published. We retrospectively examined bone imaging data in 24 patients with lipodystrophic syndromes. Twenty-two had genetic lipodystrophy: 12/22 familial partial lipodystrophy (FPLD) and 10/22 congenital generalized lipodystrophy (CGL), 8 with AGPAT2-linked CGL1 and 2 with seipin-linked CGL2. Two patients had acquired generalized lipodystrophy (AGL) in a context of non-specific autoimmune disorders. Skeletal radiographs were available for all patients, with radiographic follow-up for two. Four patients with CGL1 underwent MRI, and two of them also underwent CT. Patients with FPLD showed non-specific degenerative radiographic abnormalities. Conversely, CGL patients showed three types of specific radiographic alterations: diffuse osteosclerosis (in 7 patients, 6 with CGL1 and 1 with CGL2), well-defined osteolytic lesions sparing the axial skeleton (7 CGL1 and 1 CGL2), and pseudo-osteopoikilosis (4 CGL1). Pseudo-osteopoikilosis was the sole bone abnormality observed in one of the two patients with AGL. Osteolytic lesions showed homogeneous low signal intensity (SI) on T1-weighted and high SI on T2-weighted MR images. Most of them were asymptomatic, although one osteolytic lesion resulted in a spontaneous knee fracture and secondary osteoarthritis in a patient with CGL1. MRI also showed diffuse fatty bone marrow alterations in patients with CGL1, with intermediate T1 and high T2 SI, notably in radiographically normal areas. The three types of peculiar imaging bone abnormalities observed in generalized lipodystrophic syndromes (diffuse osteosclerosis, lytic lesions and/or pseudo-osteopoikilosis) may help clinicians with an early diagnosis in pauci-symptomatic patients.

International audience; Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m2), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Lipodystrophic syndromes are rare diseases of acquired or genetic origin, associating a decreased amount of fat (with an altered distribution of body fat in partial forms) and the metabolic alterations usually observed in obesity, i.e. insulin resistance leading to diabetes, hypertriglyceridemia with the risk of acute pancreatitis, fatty liver with risk of cirrhosis, and precocious atherosclerosis. Mutations in more than 15 genes, including LMNA, have been shown to be responsible of monogenic forms of lipodystrophies. The decreased capacity of adipocytes to store excess energy as lipids and to perform physiological endocrine functions, is considered as the main pathophysiological determinant of lipodystrophies. The low circulating levels of leptin lead to an increased appetite and participate in the ectopic storage of lipids in the muscle and liver, which aggravates the metabolic alterations. Replacement leptin therapy was shown to strikingly improve insulin resistance, dyslipidemia and liver steatosis in patients with generalized form of lipoatrophy, associated with very low endogenous secretion of leptin[1]. Recombinant leptin (metreleptin), administrated in one daily subcutaneous injection, is well-tolerated, and, although it did not improve lipoatrophy itself, demonstrated metabolic benefits in 55 lipodystrophic patients during a 3-year therapy[2]. Regarding laminopathies, two studies evaluated metreleptin therapy in 6 then 24 patients with the Dunnigan-type familial partial lipodystrophy[3,4]. Although metreleptin was efficient in decreasing circulating triglycerides and liver steatosis, the effects on glucose homeostasis did not reach statistical significance. Metreleptin, which is the first specific therapy for lipodystrophies, was approved in 2014 by the FDA for generalized forms, and is available in selected European centers through compassionate programs. Further studies are needed to clarify the therapeutic indications of metreleptin in partial lipodystrophies including laminopathies.

Objectif Les syndromes lipodystrophiques sont caracterises par une lipoatrophie generalisee ou partielle responsable d’un morphotype stigmatisant. Le traitement par leptine recombinante (une injection sous-cutanee quotidienne) ameliore les complications metaboliques associees a l’hypoleptinemie (insulino-resistance, diabete, hypertriglyceridemie). L’effet sur la qualite de vie n’a pas ete evalue. Patients et methodes Vingt patients (16 femmes, âge moyen 37,9 ± 14,9 ans), atteints d’une lipodystrophie genetique avec leptinemie Resultats L’observance du traitement est bonne chez 25 %, moyenne chez 50 % et mauvaise chez 25 % des patients. Des effets secondaires, essentiellement locaux aux points d’injection, sont rapportes dans 55 % des cas. Plus de 50 % des patients trouvent le traitement contraignant, mais rassurant et 95 % trouvent ses modalites acceptables ; 90 % notent une amelioration de leur qualite de vie sous leptine, 85 % un effet favorable sur la faim et 60 % sur leur apparence physique. Ces resultats sont significativement meilleurs en cas de bonne ou moyenne observance. Il n’y a pas de difference significative entre les patients atteints de lipodystrophie generalisee versus partielle, sauf concernant l’effet positif sur l’apparence physique (66,6 % versus 100 % respectivement, p = 0,04), chez les patients avec observance bonne ou moyenne. Discussion Le traitement par leptine ameliore la qualite de vie de 80 % des patients lipodystrophiques (100 % en cas de bonne observance) et l’apparence physique surtout en cas de lipodystrophie partielle.

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.

Glyceroneogenesis, a metabolic pathway that participates during lipolysis in the recycling of free fatty acids to triglycerides into adipocytes, contributes to the lipid-buffering function of adipose tissue. We investigated whether glyceroneogenesis could be affected by human immunodeficiency virus (HIV) protease inhibitors (PIs) responsible or not for dyslipidemia in HIV-infected patients. We treated explants obtained from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) depots from lean individuals. We observed that the dyslipidemic PIs nelfinavir, lopinavir and ritonavir, but not the lipid-neutral PI atazanavir, increased lipolysis and decreased glyceroneogenesis, leading to an increased release of fatty acids from SAT but not from VAT. At the same time, dyslipidemic PIs decreased the amount of perilipin and increased interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) secretion in SAT but not in VAT. Parthenolide, an inhibitor of the NFκB pathway, counteracted PI-induced increased inflammation and decreased glyceroneogenesis. IL-6 (100 ng) inhibited the activity of phosphoenolpyruvate carboxykinase, the key enzyme of glyceroneogenesis, in SAT but not in VAT. Our data show that dyslipidemic but not lipid-neutral PIs decreased glyceroneogenesis as a consequence of PI-induced increased inflammation in SAT that could have an affect on adipocytes and/or macrophages. These results add a new link between fat inflammation and increased fatty acids release and suggest a greater sensitivity of SAT than VAT to PI-induced inflammation.

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.

> La leptine est une adipokine produite proportionnellement au degre d’adiposite. On connait son role anorexigene, mais elle a aussi des effets pleiotropes qui modulent le metabolisme glucidolipidique. Le traitement substitutif par la leptine est un traitement de choix des anomalies metaboliques liees aux situations pathologiques rares secondaires a un deficit en leptine, soit primitif (rares mutations inactivatrices du gene ob), soit secondaire (syndromes lipoatrophiques genetiques ou acquis). En revanche, dans l’obesite commune et le diabete de type 2, la leptine s’est revelee inefficace. Recemment, plusieurs etudes menees chez des rongeurs insulino deficients suggerent que l’administration de leptine pourrait ameliorer l’effet de l’insuline dans le diabete de type 1, ouvrant la voie a des essais d’administration combinee d’insuline et de leptine chez l’homme.

Contexte/objectifs Le syndrome de Launois–Bensaude (LB) est caracterise par le developpement de masses lipomateuses de la partie superieure du corps. Des mutations de MFN2 codant la mitofusine-2, une proteine-cle de la fusion mitochondriale, ont recemment ete impliquees dans une forme autosomale recessive rare de LB. Nous decrivons le spectre clinique et les anomalies du tissu adipeux dans la plus large serie actuelle de patients atteints de LB liee a MFN2. Patients/methodes Au total, 6 patients (5 familles independantes) ont ete etudies (investigations cliniques, metaboliques, electromyogramme, imagerie, 18F-FDG-TEP-scan). Des analyses in vitro ont exploite des biopsies de lipomes (immunohistochimie, microscopie electronique, expression genique et proteique). Resultats Les patients, tous porteurs du genotype p.Arg707Trp homozygote, presentent des pseudo-lipomes mais aussi une lipoatrophie generalisee, avec hypoleptinemie majeure, hypertriglyceridemie et insulino-resistance, ainsi qu’une neuropathie de Charcot-Marie-Tooth, de severite tres variable. Le tissu lipomateux est compose d’adipocytes blancs univacuolaires, avec quelques adipocytes multivacuolaires. Il est inflammatoire (CD68+), tres vascularise (CD34+, SMA+), avec des mitochondries nombreuses, volumineuses et de structure alteree. Il presente un defaut d’expression de marqueurs d’adipocytes blancs (LEP, ADIPOQ) mais une expression marquee de certains marqueurs thermogeniques (FGF21, CITED1), en accord avec une augmentation de la consommation de glucose du tissu adipeux au 18F-FDG TEP-scan. Discussion La mutation MFN2 p.Arg707Trp homozygote induit a la fois une proliferation localisee des adipocytes et une lipoatrophie des zones non-lipomateuses, avec retentissement metabolique. Ce nouveau syndrome lipodystrophique pourrait resulter d’une alteration de la balance proliferation/differenciation des adipocytes blancs et/ou thermogeniques.

Introduction L’atteinte hypothalamo-hypophysaire (HH) au cours de la sarcoidose est rare, inferieure a 1 %, et peu decrite. L’infiltration granulomateuse peut entrainer des insuffisances antehypophysaires, une hyperprolactinemie de deconnection et un diabete insipide. L’objectif de notre travail etait de mieux decrire les atteintes HH au cours de la sarcoidose, afin d’ameliorer le diagnostic et la prise en charge. Patients et methodes Une etude multicentrique retrospective a permis d’inclure 32 patients avec une sarcoidose systemique avec atteinte HH, diagnostiques entre 1991 et 2016. Nous avons realise une analyse descriptive des donnees cliniques, biologiques, hormonales et radiologiques. Resultats Parmi les 32 patients inclus, il y avait 18 femmes et 14 hommes. L’âge moyen au diagnostic de sarcoidose HH etait de 40,5 ans (± 13,4). La majorite des patients (n = 29) presentaient des symptomes compatibles avec un dysfonctionnement hormonal : asthenie (n = 19), amenorrhee (n = 12/14 femmes en âge de procreer), dysfonction erectile et/ou diminution de la libido (n = 10/14 hommes). Trente et un patients avaient une insuffisance antehypophysaire : 25 deficits gonadotropes (78 %), 20 deficits thyreotropes (65 %), 11 deficits somatotropes (46 %) et 2 deficits corticotropes. Presque la moitie des patients (n = 15) avait un diabete insipide, dont 1 seul cas d’hypernatremie a 149 mmol/L. Une hyperprolactiemie a ete mesuree chez 24 patients (77 %). Un syndrome hypothalamique a ete retrouve chez 6 patients (19 %), caracterise par une prise de poids massive en quelques mois (mediane 22 kg). Des anomalies radiologiques etaient quasi constantes sur l’IRM (n = 31) : epaississement focal ou diffus de la tige pituitaire (n = 20), infiltration de l’hypothalamus ou du plancher du 3e ventricule (n = 17), anomalies hypophysaires (n = 11). Tous les patients avaient une sarcoidose multisystemique avec comme localisations principales : ganglionnaire (n = 24), pulmonaire (n = 23) et neurologique (n = 18), dont 5 patients asymptomatiques avec des anomalies IRM isolees. Les atteintes ORL etaient frequentes avec une localisation naso-sinusienne pour 10 patients (31 %) et 9 cas de parotidites (28 %). L’enzyme de conversion etait augmentee dans 68 % des cas (n = 19/28) et 3 patients avaient une hypercalcemie. Le diagnostic histologique de sarcoidose a ete etabli pour 26 patients. La quasi-totalite des patients a ete traitee par corticotherapie (n = 29), le plus souvent en association avec un autre immunosuppresseur (n = 20) : methotrexate (n = 11), infliximab (n = 7) ou mycophenolate mofetil (n = 5). La duree moyenne de suivi etait de 10 ans (± 7,5). Parmi les patients recontroles sur le plan hormonal : 11 avaient une prolactine normalisee (58 %), 8 avaient recupere une fonction gonadotrope (30 %) et 1 seul avait recupere sa fonction thyreotrope. Aucune guerison de diabete insipide n’a ete rapportee. Seuls 10 patients (31 %) etaient consideres en remission de leur sarcoidose a la fin du suivi. Conclusion Les deficits gonadotrope, thyreotrope et l’hyperprolactinemie sont les atteintes les plus frequentes dans notre etude realisee sur la plus grande cohorte de sarcoidose HH. Une recuperation de la fonction gonadotrope a ete observee dans 30 % des cas apres traitement. La moitie des cas presente un diabete insipide definitif. Les patients avec atteinte HH ont tous une sarcoidose multisystemique, et il semblerait que les localisations naso-sinusiennes et parotidiennes soient plus frequentes.

International audience; Semicarbazide-sensitive amine oxidase (SSAO), an enzyme highly expressed on adipocyte plasma membranes, converts primary amines into aldehydes, ammonium and hydrogen peroxide, and is likely involved in endothelial damage during the course of diabetes and obesity. We investigated whether in vitro, adipocyte SSAO was modulated under hypoxic conditions that is present in adipose tissue from obese or intensive care unit. Physical or pharmacological hypoxia decreased SSAO activity in murine adipocytes and human adipose tissue explants, while enzyme expression was preserved. This effect was time-, dose-dependent and reversible. This down-regulation was confirmed in vivo in subcutaneous adipose tissue from a rat model of hypoxia. Hypoxia-induced suppression in SSAO activity was independent of the HIF-1-α pathway or of oxidative stress, but was partially antagonized by medium acidification. Hypoxia-induced down-regulation of SSAO activity could represent an adaptive mechanism to lower toxic molecules production, and may thus protect from tissue injury during these harmful conditions.

With the escalating incidence of massive obesity and evidence for visceral fat being implicated in cardiometabolic risk, better phenotyping of patients is necessary to develop personalized medicine. Massive obesity is difficult to explore and little is known about the importance of visceral fat in the massively obese population and their cardiometabolic risk. Numerous techniques have been developed to assess visceral fat but very few have been validated in morbidly obese population. Neck circumference is an interesting clinical parameter in such patients. Computed tomography and magnetic resonance imaging are the best physical methods to assess abdominal obesity and to distinguish between subcutaneous and visceral abdominal tissues, but these methods have technical limits when applied for assessing massive obesity. Combining biological and radiological parameters in an adipo-inflammation score could help to define the importance of abdominal obesity in morbidly obese subjects. New indicators of visceral fat (histological and cardiovascular markers) have recently emerged.

Introduction Les insulinomes sont des tumeurs malignes dans 5 a 10 % des cas. Leurs localisations secondaires sont principalement ganglionnaires et hepatiques. Nous rapportons le cas d’un insulinome avec metastases ovariennes. Observation Une patiente de 67 ans, diabetique de type 2 traitee par Metformine presentait depuis 2 mois des hypoglycemies a repetition. Les taux d’insulinemie, de peptide C et de pro-insuline ont affirme le diagnostic d’hypoglycemie organique. Le scanner abdominal et l’IRM ont identifie un nodule de 25 mm associe a une thrombose portale et un volumineux ovaire droit (7 cm). La ponction sous echo-endoscopie etait en faveur une tumeur neuro-endocrine pancreatique bien differenciee. Les marqueurs tumoraux ovariens etaient negatifs. La TEP-FDG a identifie une fixation du thrombus et une fixation tres moderee pancreatique et ovarienne. La TEP DOTATOC a montre une intense fixation pancreatique, du thrombus et de la masse ovarienne droite. Une splenopancreatectomie gauche avec thrombectomie, tumorectomie du segment IV du foie et annexectomie bilaterale a ete realisee. L’examen anatomopathologique a confirme une tumeur neuro-endocrine de 4 cm assez bien differenciee de la queue du pancreas. Elle s’accompagne d’engainements peri-nerveux, d’emboles neoplasiques intravasculaires, d’un thrombus tumoral porte, d’un envahissement de la paroi gastrique, de metastases ganglionnaires et ovariennes bilaterales (pT4N1M1), et d’une metastase hepatique du segment IV. Le traitement antidiabetique a ete repris. Une surveillance a 3 mois par TEP DOTATOC et scanner abdominopelvien est prevue. Conclusion L’insulinome malin avec localisations ovariennes est exceptionnel. Ce cas illustre l’interet de la TEP DOTATOC qui a permis la detection des localisations metastatiques.

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.

Adipose tissue has long been considered as an “organ” of energy storage but it is also capable of synthesizing and releasing various factors called adipokines, such as adiponectin. Adiponectin is the most abundant adipose tissue transcript that displays insulin sensitizing and anti-inflammatory properties. The complexity of adiponectin multi-functionality is illustrated in kidney diseases, where plasma hormone levels predict fatal issue, despite its antiinflammatory, anti-atherogenic, and insulin-sensitizing properties. This is also highlighted in severe forms of insulin resistance in patients with receptor dysfunction who present elevated adiponectinemia, whereas patients with common form of insulin resistance have low adiponectin levels. Finally, the role of adiponectin in carcinogenesis and in other physiological and pathological contexts is described.

Introduction Le cortico-surrenalome est une tumeur neuro-endocrine rare : 0,5 a 2 cas pour un million. Le signe clinique le plus frequent est le syndrome de cushing (50 %), puis l’hyperandrogenie avec virilisation (21 %). Les formes feminisantes sont plus rares : 8 % et sont decrites principalement chez des hommes. Observation La patiente, G1P1, menopausee a l’âge de 56 ans, a consulte a 65 ans, pour des metrorragies intenses, d’apparition brutale. A l’echographie : hypertrophie endometriale de 16 mm (n Au bilan hormonal : estradiol eleve a 722 pmol/L (n Au scanner : masse surrenalienne droite de 5,5 cm de grand axe, heterogene, de densite 87 UH. L’examen anatomopathologique apres surrenalectomie concluait a un cortico-surrenalome de 5 cm, score de Weiss a 7. Apres la chirurgie, les metrorragies se sont spontanement resolues et le bilan hormonal s’est normalise. Un traitement hormonal par mitotane a ete instaure. A trois mois post-operatoire, le PET-scan etait negatif. Discussion Ce cas clinique montre une presentation atypique d’un cortico-surrenalome, se revelant par des metrorragies. Il s’agit d’un cas tres rare car a notre connaissance, seulement deux cas ont ete decrits chez des femmes menopausees.

Introduction Les syndromes lipodystrophiques d'origine genetique ou acquise se caracterisent principalement par une lipoatrophie generalisee ou partielle associee a une insulinoresistance severe, une steatose hepatique, une hypertriglyceridemie et une hypoleptinemie. Le traitement par leptine recombinante (metreleptine) ameliore les parametres metaboliques chez ces patients. Nous avons teste l'effet du traitement par metreleptine sur les concentrations de PCSK9 (proprotein convertase subtilisin kexin type 9), un inhibiteur endogene du recepteur au LDL. Patients et Methodes Seize patients diabetiques lipodystrophiques (formes generalisees, n =5 ; formes partielles, n =11) ont ete inclus dans cette etude et le bilan metabolique a ete realise avant et apres 12 mois de traitement par leptine. Le traitement hypolipidemiant est reste stable pendant cette periode. Les dosages seriques (triplicats) de PCSK9 ont ete realises a jeun grâce a un test ELISA (Cyclex©). La sensibilite a l'insuline a ete mesuree au cours de clamps hyperinsulinemiques-euglycemiques (M value). Resultats Les patients avaient en moyenne 37 ans, un IMC de 23,3kg/m 2 et 15,1 % de masse grasse. Le traitement par leptine a significativement ameliore l'HbA 1c (8,8 % a M0 vs 7,6 % a M12, p =0,009), la sensibilite a l'insuline : M value (3,04 vs 5,52, p =0,005) le LDL-cholesterol (1,07 vs 0,78g/L, p =0,007), les triglycerides (5,42 vs 3,16g/L, p =0,04) et les ASAT (51,9 vs 35,0 UI/l, p =0,03). Les concentrations de PCSK9 ont egalement diminue de 25 % sous leptine (304 vs 229ng/ml ; p =0,02). La baisse de PCSK9 entre MO et M12 est significativement correlee a la baisse de l'apolipoproteine B ( p =0,004). La baisse de PCSK9 tend egalement a etre associee a l'augmentation de l'insulinosensibilite sous leptine ( p =0,06). Conclusions Cette etude demontre pour la premiere fois que le traitement par leptine diminue les concentrations de PCSK9 chez les patients lipodystrophiques. Cette baisse de PCSK9 pourrait contribuer en partie a l'amelioration du bilan lipidique chez ces patients. Cette etude suggere l'existence d'une regulation de PCSK9 par la leptine.

Introduction Le traitement par leptine recombinante humaine (metreleptine) ameliore les parametres metaboliques chez les patients atteints de syndromes lipodystrophiques. Ses effets sur la structure du tissu adipeux et sur l'inflammation systemique n'ont pas ete etudies. Patients et Methodes Dix-huit patients diabetiques atteints de lipodystrophie partielle ( n =12, mutations LMNA dans 9 cas) ou generalisee ( n =6, mutations d'AGPAT2 dans 5 cas) severement hypoleptinemiques ont ete inclus dans un programme compassionnel. Les parametres metaboliques, inflammatoires et les scores de steatose et de fibrose hepatique ont ete mesures. Une biopsie de tissu adipeux sous-cutane abdominal a ete realisee chez 10 patients, avant et un an apres traitement. Les caracteristiques histologiques, dont la presence de macrophages ainsi que l'expression des transcrits des facteurs de transcription adipocytaires ont ete etudies en parallele de celles du tissu adipeux de cinq controles. Resultats Le traitement a permis une diminution de l'HbA 1c , des triglycerides, et une amelioration de l'insulino-sensibilite. De plus, il a permis une diminution significative des concentrations seriques de CRPus, d'orosomucoide et de ferritine. Il induit une amelioration des enzymes hepatiques, des scores de steatotest et defibrotest, marqueurs de steatose et de fibrose hepatiques respectivement. Le tissu adipeux des patients lipodystrophiques, compare a du tissu adipeux sous-cutane temoin, est constitue de lobules dystrophiques desorganises, presentant des adipocytes de taille heterogene et une fibrose etendue. L'expression des facteurs de transcription adipocytaires PPARG et SREBP 1c est diminuee dans le tissu adipeux des patients alors que. l'infiltration macrophagique, evaluee par immunomarquage CD68 et CD163, est augmentee. Apres un an de traitement par metreleptine, les anomalies de structure et d'expression ne sont pas significativement modifiees. En revanche, l'infiltration macrophagique des tissus adipeux lipoatrophiques, est significativement diminuee. Conclusions Le traitement par metreleptine ameliore non seulement les parametres metaboliques mais egalement les parametres inflammatoires adipocytaires, hepatiques et systemiques chez les patients lipodystrophiques. Cette baisse pourrait contribuer a l'amelioration des parametres metaboliques.

Thrombotic risk, that is partly related to a disturbed adipokine/cytokine profile, is strongly increased in obese and type 2 diabetic patients and. Apelin is an adipokine with pleiotropic function and cardiovascular fluid, and energetic homeostasis, and acts through the APJ transmembrane receptor. In this project, we show for the first time that apelin displays a potent antithrombotic effect The antithrombotic effect is APJ- mediated and requires the proteolytic maturation of apelin. Apelin strongly inhibits thrombin- or collagen- induced platelet aggregation, independently of ADP secretion. It prevents platelet activation and thrombin-activated intracellular signaling pathways. As a consequence, in mice models, intravenous apelin injection increases tail-bleeding time and delays chemically- induced vessel occlusion and thrombus stabilization. We also determined that functional APJ is strongly over-expressed in platelet from obese subjects or mice (DIO mice, db/db), but apelin preserved its antithrombotic function during these metabolic disorder conditions. In conclusion, in this original study, we enlighten a new biological function of apelin that could be considered as a new strategy to reduce the increased risk of thrombosis in patients with metabolic disorders.

Physical activity has been shown to increase following obesity surgery; however, changes in sedentary behavior in this setting are not known. Our aim was to describe changes in both physical activity and sedentary behavior of obese patients after gastric bypass (GBP) and their relationships with changes in body composition.Physical activity, time spent watching TV as typical sedentary behavior (self-report), and body composition (DXA) were assessed before and 6 and 12 months after GBP in 86 obese patients (67 women, 24-66 years old, BMI 41.3-53.5 kg/m(2)).One year after GBP (mean loss of weight -37.1 kg, fat mass -25.7 kg, lean body mass -9.4 kg), leisure-time physical activity (LTPA) significantly increased from 2.0 (SD 3.7) to 3.8 (5.4) h/week and from 7.2 (12.5) to 14.1 (20.1) MET-h/week (MET: metabolic equivalent task), the number of LTPA performed increased from 1.3 (1.3) to 1.8 (1.4), and TV time decreased from 3.0 (1.6) to 2.4 (1.4) h/day (all p 0.05). The ranking of the most frequently performed LTPA did not change. Positive associations were observed between the increase in lean body mass and (1) the increase in LTPA and (2) the decrease in TV watching. Inverse relationships were found for changes in fat mass.Together with increased LTPA, this study shows a decrease in sedentary behavior after GBP, which appears related to favorable changes in body composition. These observations are important to design future intervention studies, including physical activity and sedentary occupations aiming to optimize the care of patients after bariatric surgery.

International audience; Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.

Background Preventing or slowing the progression of prediabetes to diabetes is a major therapeutic issue. Objectives Our aim was to evaluate the effects of 4-month treatment with a dietary supplement containing cinnamon, chromium and carnosine in moderately obese or overweight pre-diabetic subjects, the primary outcome being change in fasting plasma glucose (FPG) level. Other parameters of plasma glucose homeostasis, lipid profile, adiposity and inflammatory markers were also assessed. Methods In a randomized, double-blind, placebo-controlled study, 62 subjects with a FPG level ranging from 5.55 to 7 mmol/L and a body mass index ≥25 kg/m2, unwilling to change their dietary and physical activity habits, were allocated to receive a 4-month treatment with either 1.2 g/day of the dietary supplement or placebo. Patients were followed up until 6 months post-randomization. Results Four-month treatment with the dietary supplement decreased FPG compared to placebo (-0.24±0.50 vs +0.12±0.59 mmol/L, respectively, p = 0.02), without detectable significant changes in HbA1c. Insulin sensitivity markers, plasma insulin, plasma lipids and inflammatory markers did not differ between the treatment groups. Although there were no significant differences in changes in body weight and energy or macronutrient intakes between the two groups, fat-free mass (%) increased with the dietary supplement compared to placebo (p = 0.02). Subjects with a higher FPG level and a milder inflammatory state at baseline benefited most from the dietary supplement. Conclusions Four-month treatment with a dietary supplement containing cinnamon, chromium and carnosine decreased FPG and increased fat-free mass in overweight or obese pre-diabetic subjects. These beneficial effects might open up new avenues in the prevention of diabetes. Trial Registration ClinicalTrials.gov NCT01530685

Background Lipodystrophic syndromes are a heterogeneous group of genetic or acquired disorders characterized by a generalized or partial loss of body fat with severe metabolic complications linked to insulin resistance and dyslipidemia. Specific radiographic bone features have been described in isolated cases or small cohorts of patients. Objectives To describe the bone imaging features of lipodystrophies in the largest cohort ever published. Methods Twenty-four patients with lipodystrophic syndromes followed in our reference center with available bone imaging were studied. Twenty-two had genetic lipodystrophies (12/22 familial partial lipodystrophies (FPL, linked to mutations in LMNA encoding lamin A/C (n=9), PPARG encoding PPARg (n=2), or PLIN encoding perilipin (n=1)) and 10/22 congenital generalized lipodystrophies ( AGPAT2 -linked CGL1 (n=8) or CGL2 due to seipin mutations (n=2)). Two had acquired generalized lipodystrophies (AGL) in a context of non-specific autoimmune disorders. They were retrospectively reviewed in consensus by 2 senior musculo-skeletal radiologists, 3 rheumatologists and 1 endocrinologist. Standard bone X-rays were available for all of them with a radiographic follow-up for 2 of them. Four patients underwent magnetic resonance imaging (MRI) and two computed tomography (CT). Results All FPL patients (n=12, 11 women, mean age 45 years (±14, SD) had non-specific radiographic abnormalities. In CGL patients (n=10, 7 women, mean age 30 years (±18, SD), we observed three types of radiographic alterations: 7 patients (6 CGL1 and 1 CGL2) had diffuse osteosclerosis, eight (7 CGL1 and 1 CGL2) had one or several well-characterized lytic bone lesions and 4 (4 CGL1) had pseudo-osteopoikilosis (figure). Lytic lesions usually involved the epiphysis as well as the metaphysis in the proximal (n=7) and distal femur (n=6), the proximal tibiae (n=6) and the distal humerus (n=6). Additionally, 5 patients, all with lytic lesions, had honeycomb multikystic lesions that appeared between age of 2 and 14 in one. In AGL, pseudo-osteopoikilosis was the sole bone abnormality observed in one of the 2 patients. MRI examination showed that lytic lesions were homogeneous with low T1 and high T2 signal. The 4 CGL patients who underwent a MRI had diffuse fatty bone marrow alterations with intermediate T1 and high T2 signal, notably in radiographically normal areas, as observed in anorexia, suggesting a serous transformation of bone marrow. Only one CGL1 patient had a symptomatic lytic lesion, which resulted in a spontaneous knee fracture and subsequent secondary osteoarthritis. Conclusions The most frequent imaging abnormalities seen in generalized lipodystrophic syndromes are diffuse osteosclerosis, lytic lesions and/or pseudo-osteopoikilosis. These bone abnormalities are more frequently associated with AGPAT 2 than seipin mutations. Diffuse MRI abnormalities in fatty bone marrow suggest that this fat tissue is disturbed. These features, the pathophysiology of which is poorly understood, may help clinicians for an early diagnosis in pauci-symptomatic patients. Disclosure of Interest None declared

Objectif La glucocorticotherapie (GC) au long cours s’associe souvent a une redistribution du tissu adipeux (TA) dont la physiopathologie reste inconnue. L’objectif de ce travail est de comparer les profils d’adipokines/cytokines et d’inflammation du TA chez des patients traites par GC, developpant ou non une lipodystrophie induite par les GC (LIG). Materiels et methodes Des adultes, necessitant un traitement systemique a forte dose de prednisone pour au moins 3 mois ont ete inclus. Les prelevements sanguins et biopsies de TA sous-cutane abdominal ont ete recueillis avant (M0) et a 3 mois (M3) de traitement. La presence/l’absence de LIG etait determinee sur des photographies standardisees et prealablement validees. Resultats 32 patients (âge moyen 61 ± 22 ans, 75% de femmes) ont ete inclus. A M3, 15 sont LIG + et 15 LIG –. L’IMC, le rapport tour de taille/tour de hanche et l’index d’adiposite basales sont identiques chez les LIG+ et les LIG –, de meme que les marqueurs inflammatoires (CRP, IL-6, TNFR1s) qui diminuent de facon similaire dans les deux groupes. La leptinemie basale est superieure (20,8 ± 15,2 vs 8,5 ± 10,5 μg/l, p = 0,006) et la resistinemie inferieure (10,1 ± 6,6 15,5 ± 11,3 μg/l, p = 0,05) chez les LIG+. Surtout, la leptinemie a M0 est predictive de survenue de LIG pour une valeur seuil de leptinemie a 5,9 μg/l a M0 avec une sensibilite de 93% et une specificite de 60% (en courbe ROC, AUC 0,8%, p Conclusion LIG est associee a un profil d’adipokine different a la fois avant et apres traitement par glucocorticoides. La leptinemie avant traitement par glucocorticoides est predictive de la survenue de LIG.

Introduction Les syndromes lipodystrophiques s’associent a une insulino-resistance, une hypertriglyceridemie et une steatose hepatique souvent severes. La perte de tissu adipeux s’accompagne d’un deficit en leptine serique, qui pourrait participer a l’accumulation de lipides dans les tissus illegitimes. Plusieurs essais de substitution par la leptine ont montre une amelioration de l’insulino-resistance. L’objectif du programme est d’evaluer les effets du traitement par la leptine sur la secretion insulinique, les fonctions du tissu adipeux et les regulations endocrines chez les patients diabetiques porteurs de lipodystrophies. Patients et methodes La leptine, fournie gracieusement par le laboratoire Amylin (CA, USA), est administree en une injection sous-cutanee par jour (0,02 a 0,12 mg/kg), dans le cadre d’une autorisation temporaire d’utilisation (ATU) chez des patients porteurs de lipodystrophies partielles ou generalisees et deficients en leptine. A J0 et M12 de traitement sont evalues l’insulinosecretion (HGPO et perfusion de glucose par paliers couplee a un test a l’arginine), la sensibilite a l’insuline (clamp euglycemique hyperinsulinemique a 2 paliers), la composition corporelle (DEXA), les surfaces de tissu adipeux sous-cutane et visceral et l’intensite de la steatose hepatique (scanner abdominal), les fonctions adipocytaires (biopsie de tissu adipeux) et les differents axes endocriniens. Tous les 3 mois sont evalues: mesures anthropometriques, HbA1c, bilan lipidique, bilan hepatique, leptine et anticorps anti-leptine circulants. Resultats Entre janvier et novembre 2010, 10 patients ont ete inclus. Chez les 3 patientes qui ont recu 9 mois de traitement, celui-ci a ete bien tolere, a ameliore l’equilibre du diabete (reduction des doses d’antidiabetiques oraux et/ou amelioration de l’HbA1c), le bilan hepatique et a induit une perte ponderale de 3 a 6 kg. La triglyceridemie s’est amelioree chez 2 d’entre elles. Conclusion Ces premiers resultats confirment l’interet de la leptine dans ce type de diabete. Nous esperons pouvoir traiter grâce a ce programme 30 patients adultes.

Introduction Chez le patient diabetique, les « pics » hyperglcemiques post-prandiaux pourraient contribuer a la genese de l’atherosclerose. La dysfonction endotheliale induite par l’hyperglycemie fait tres vraisemblablement intervenir des phenomenes de stress oxydatif. Ces excursions hyperglycemiques sont en general trop transitoires pour influencer de facon significative l’equilibre glycemique moyen (HbA1c). L’objectif principal etait d’evaluer chez des patients diabetiques de type 1 (DT1) l’influence du moment de l’injection d’analogue rapide (pre- ou post-prandiale) sur l’amplitude du stress oxydatif quantifie par les isoprostanes urinaires Materiels et methodes 18 patients diabetiques de type 1, âges de 36,4 (± 8,6) ans, maitrisant l’insulinotherapie fonctionnelle, suivis pendant une periode de 6 mois de facon etroite grâce au carnet glycemique electronique dont ils etaient munis, randomises suivant un schema therapeutique en cross-over sur 2 periodes successives de 3 mois d’analogue ultrarapide, injecte soit en pre-prandial, soit en post-prandial une heure apres le debut du repas. Resultats La valeur d’HbA1c etait a l’entree de l’etude de 7,3 (± 0,7) %, de 7,44 %[IC : 7,02 ; 7,85] apres la sequence de 3 mois en injection pre-prandiale, et de 7.90 %[7.48 ; 8,31] apres celle en injection post-prandiale (p = 0,086). La difference entre la glycemie post-prandiale et la glycemie a jeun etait de 0,66 [0,30 ; 1,02] g/l pendant la periode d’injection pre-prandiale, et de 0,98 [0,64 ; 1,31] g/l en periode d’injection pre-prandiale, soit un delta de 0,31 [–0,05 ; 0,68] (p = 0,0850). Le dosage des isoprostanes urinaires etait de 37,10 [31,96 ; 42,24] pmol/mmolcreatinine pendant la periode d’injection pre-prandiale et de 36,74 [31,60 ; 41,89] en periode d’injection post prandiale (p = 0,9160). Conclusion Chez des DT1 en equilibre glycemique moyen controle, le moment pre- ou post-prandial de l’injection d’analogue ultrarapide, meme s’il tend a augmenter les excursions hyperglycemqiues, ne majore pas de facon significative le stress oxydatif. Ceci serait un argument en faveur de la flexibilite du traitement par analogues rapides.

Objective: Experimental endotoxaemia induces subcutaneous adipose tissue inflammation and systemic insulin resistance in lean subjects. Glyceroneogenesis, by limiting free fatty acids (FFA) release from adipocytes, controls FFA homoeostasis and systemic insulin sensitivity. The roles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in metabolic deregulation are intrinsically different. We compared the effect of lipopolysaccharide (LPS) on the inflammation profiles of SAT and VAT explants from lean women, as well as on glyceroneogenesis, to test whether these two fat depots have intrinsically different responses to this metabolic endotoxin. Design: Abdominal SAT and VAT explants from eight lean women were treated in vitro with LPS. Their inflammatory status was evaluated by cytokine gene expression and secretion; glyceroneogenesis was evaluated by cytosolic phosphoenolpyruvate carboxykinase activity and FFA vs glycerol release. Results: In the basal state, the cytokine status and expression of macrophage markers were lower in SAT than VAT. In the presence of 100 ng ml−1 LPS, SAT exhibited a strong inflammatory response (increased interleukin-6 and tumor necrosis factor-α expression) and increased release of FFA due to inhibition of glyceroneogenesis, whereas VAT was only mildly affected. The effects of LPS on both tissues were blocked by the nuclear factor-κB (NF-κB) inhibitor, parthenolide. A significant effect of LPS on VAT occurred only at 1 μg ml−1 LPS. Conclusion: SAT explants from lean women are more sensitive to LPS-induced NF-κB activation than are VAT explants, leading to a depot-specific dysfunction of FFA storage. As SAT is the major player in FFA homoeostasis, this SAT dysfunction could be associated with visceral fat hypertrophy and systemic lipid disorders.

Introduction Le risque de thrombose arterio-veineuse est fortement accru chez les patients obeses et/ou atteints de diabete de type 2. Cette etude met en evidence pour la premiere fois les effets antiagregants plaquettaires et antithrombotiques de l'apeline, une adipokine connue par ailleurs pour ameliorer la tolerance au glucose. Materiels et methodes Methodologie : les effets de l'apeline sur l'agregation plaquettaire et des modeles de thrombose ont ete etudies par des approches in vivo et in vitro , a la fois chez l'homme et la souris. Resultats Les plaquettes humaines et murines expriment l'apeline et son recepteur APJ (ARN et proteine). Sur des modeles murins evalues in vivo, des experiences de temps de saignement et de thrombose induite par lesion chimique montrent que l'injection d'apeline induit : i)un allongement du temps de saignement (souris temoins et obeses) ii)un retard significatif de l'occlusion des vaisseaux (formation de thrombi instables). Ces effets sur la formation de thrombi sont confirmes in vitro. i)dans un modele de chambre de perfusion sur matrice de collagene en conditions de flux sanguin dans lequel l'apeline diminue la taille des thrombi de 59±13 %. ii)l'apeline inhibe l'agregation plaquettaire induite par le collagene ou la thrombine chez des sujets temoins ou obeses, soulignant le caractere antiagregant de l'apeline. Ces effets sont associes a une diminution de l'activation des voies de signalisation ERK1/2, p38, PI3K/Akt et de la mobilisation calcique. Conclusion En conclusion, cette etude montre pour la premiere fois les proprietes antiagregants et anti-thrombotiques de l'apeline, qui sont conservees au cours du syndrome metabolique. Compte tenu de ses autres proprietes metaboliques et cardiovasculaires favorables, le systeme apelinergique constitue ainsi une cible pertinente dans la prise en charge du risque metabolique et cardio-vasculaire au cours du syndrome metabolique.