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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is a common metabolic disorder. It plays an important role in the metabolic syndrome (or syndrome X), type 2 diabetes, obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the insulin transduction pathways. Mutations of the insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of insulin resistance, as attested by the clinical characteristics of lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the familial partial lipodystrophy of the Dunnigan type, due to mutations of the lamin A/C gene, and the congenital generalized lipodystrophy, linked to alterations in the protein seipin. However, their physiopathology remains mysterious. Lamin A/C is indeed an ubiquitous nuclear protein, which is also mutated in a genetic squelettic and/or cardiac myopathy, and seipin is a protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular lipodystrophies which can be considered as caricatural models of the metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of insulin resistance.
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PMID:[Major insulin resistance syndromes: clinical and physiopathological aspects]. 1183 62

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by marked lack of body fat since birth, which results in striking muscular appearance. Patients develop extreme insulin resistance and its complications, such as diabetes, hyperlipidemia and fatty liver. Mutations in the BSCL2 (which encodes seipin, a protein of unknown function) and AGPAT2 (which encodes 1-acylglycerol-3-phosphate O-acyltransferase 2) genes have been reported in patients with CGL. AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders. All enzymes involved in triglyceride synthesis, including AGPAT, have several known isoforms encoded by different genes. Assuming different substrate specificities of these enzymes, the human body might have many forms of triglycerides and phospholipids. Here, we discuss the significance of these in energy storage, in addition to the normal functioning of cell membranes.
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PMID:Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. 1282 27

Insulin resistance is common and plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). Precedents in biomedical research indicate that evaluation of monogenic syndromes can help to understand a common complex phenotype. Monogenic forms of insulin resistance, such as familial partial lipodystrophy, which results from mutations in either LMNA (encoding lamin A/C) or PPARG (encoding peroxisome proliferator-activated receptor gamma), and congenital generalized lipodystrophy, which results from mutations in either AGPAT2 (encoding 1-acylglycerol-3-phosphate O-acyltransferase) or BSCL2 (encoding seipin), can display features seen in the common metabolic syndrome. In addition, insulin resistance is seen in disorders associated with insulin receptor mutations, progeria syndromes and in inherited forms of obesity. Although insulin resistance in such rare monogenic syndromes could simply be secondary to fat redistribution and/or central obesity, the products of the causative genes might also produce insulin resistance directly, and might illuminate new causative mechanisms for insulin resistance in such common disorders as T2DM and obesity.
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PMID:Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome. 1451 35

Lack of adipose tissue, either complete or partial, is the hallmark of disorders known as lipodystrophies. Patients with lipodystrophies suffer from metabolic complications similar to those associated with obesity, including insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The loss of body fat in inherited lipodystrophies can be caused by defects in the development and/or differentiation of adipose tissue as a consequence of mutations in a number of genes, including PPARG (encoding a nuclear hormone receptor), AGPAT2 (encoding an enzyme involved in the biosynthesis of triglyceride and phospholipids), AKT2 (encoding a protein involved in insulin signal transduction), and BSCL2 (encoding seipin, whose role in the adipocyte biology remains unclear). The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of inherited lipodystrophies as they relate to adipocyte biology and their associated phenotypic manifestations.
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PMID:Genetic disorders of adipose tissue development, differentiation, and death. 1672 6

Malfunctions of processes involved in cellular lipid storage and mobilization induce the pathogenesis of prevalent human diseases such as obesity, type 2 diabetes and atherosclerosis. Lipid droplets are the main lipid storage depots for neutral lipids in eukaryotic cells, and as such fulfil an essential function to balance cellular lipid metabolism and energy homeostasis. Despite significant progress in identifying key metabolic enzymes involved in lipid storage and their regulation in various model organisms, some fundamental questions as to the biogenesis, subcellular distribution and inheritance of lipid droplets are as yet unsolved. In this study, we applied a set of imaging techniques such as high-resolution four-dimensional (4D) live-cell imaging, quantitative microscopy, transmission electron microscopy and electron tomography to gain insight into the spatio-temporal organization of lipid droplets during cellular growth in the yeast Saccharomyces cerevisiae. This analysis revealed a high level of organization of the subcellular positioning of lipid droplets in individual cells, their directed migration towards the cellular periphery and a coordinated transfer of a subpopulation of lipid droplets into daughter cells during cell division. Lipid droplets appear to remain associated with ER membranes during cellular growth independently of their size and subcellular localization. Deletion of FLD1, the functional orthologue of the human BSCL2 gene encoding seipin, leads to impaired dynamics of yeast lipid droplets and defective lipolysis, which might be due to aberrant ER structures in these mutants. Our data suggest a role for yeast seipin as a scaffolding protein that is required for the dynamics of a specific subdomain of the ER, and provide a new aspect for the interpretation of abnormal lipid droplets phenotypes in yeast mutants lacking seipin.
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PMID:A role for seipin in lipid droplet dynamics and inheritance in yeast. 2210 Sep 22

The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, dependent on pathophysiological advances, which today tend to classify genetically determined lipodystrophy as being related to laminopathy or to lipid droplet disorders.
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PMID:How to diagnose a lipodystrophy syndrome. 2274 2

Brown adipose tissue (BAT) plays a key role in thermogenesis to protect the body from cold and obesity. White adipose tissue (WAT) stores excess energy in the form of triglycerides. To better understand the genetic effect on regulation of WAT and BAT, we investigated the fat fraction (FF) in two types of adipose tissues in ob/ob, human BSCL2/seipin gene knockout (SKO), Fsp27 gene knockout (Fsp27(-/-)), and wild-type (WT) mice in vivo using chemical shift selective imaging and (1)H-MR spectroscopy. We reported that the visceral fat volume in WAT was significantly larger in ob/ob mice, but visceral fat volumes were lower in SKO and Fsp27(-/-) mice compared with WT mice. BAT FF was significantly higher in ob/ob mice than the WT group and similar to that of WAT. In contrast, WAT FFs in SKO and Fsp27(-/-) mice were lower and similar to that of BAT. The adipocyte size of WAT in ob/ob mice and the BAT adipocyte size in ob/ob, SKO, and Fsp27 mice were significantly larger compared with WT mice. However, the WAT adipocyte size was significantly smaller in SKO mice than in WT mice. Positive correlations were observed between the adipocyte size and FFs of WAT and BAT. These results suggested that smaller adipocyte size correlates with lower FFs of WAT and BAT. In addition, the differences in FFs in WAT and BAT measured by MR methods in different mouse models were related to the different regulation effects of ob, seipin, or Fsp27 gene on developing WAT and BAT.
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PMID:Comparison of brown and white adipose tissue fat fractions in ob, seipin, and Fsp27 gene knockout mice by chemical shift-selective imaging and (1)H-MR spectroscopy. 2314 22

Obesity impairs male fertility, providing evidence for a link between adipose tissue and reproductive function; however, potential consequences of adipose tissue paucity on fertility remain unknown. Lack of s.c. fat is a hallmark of Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), which is caused by mutations in BSCL2-encoding seipin. Mice with a targeted deletion of murine seipin model BSCL2 with severe lipodystrophy, insulin resistance, and fatty liver but also exhibit male sterility. Here, we report teratozoospermia syndrome in a lipodystrophic patient with compound BSCL2 mutations, with sperm defects resembling the defects of infertile seipin null mutant mice. Analysis of conditional mouse mutants revealed that adipocyte-specific loss of seipin causes progressive lipodystrophy without affecting fertility, whereas loss of seipin in germ cells results in complete male infertility and teratozoospermia. Spermatids of the human patient and mice devoid of seipin in germ cells are morphologically abnormal with large ectopic lipid droplets and aggregate in dysfunctional clusters. Elevated levels of phosphatidic acid accompanied with an altered ratio of polyunsaturated to monounsaturated and saturated fatty acids in mutant mouse testes indicate impaired phospholipid homeostasis during spermiogenesis. We conclude that testicular but not adipose tissue-derived seipin is essential for male fertility by modulating testicular phospholipid homeostasis.
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PMID:Lack of testicular seipin causes teratozoospermia syndrome in men. 2552 9

Genetic research has revealed pro-opiomelanocortin (POMC) to be a fundamental regulator of energy balance and body weight in mammals. Within the brain, POMC is primarily expressed in the arcuate nucleus of the hypothalamus (ARC), while a smaller population exists in the brainstem nucleus of the solitary tract (POMCNTS). We performed a neurochemical characterization of this understudied population of POMC cells using transgenic mice expressing green fluorescent protein (eGFP) under the control of a POMC promoter/enhancer (PomceGFP). Expression of endogenous Pomc mRNA in the nucleus of the solitary tract (NTS) PomceGFP cells was confirmed using fluorescence-activating cell sorting (FACS) followed by quantitative PCR. In situ hybridization histochemistry of endogenous Pomc mRNA and immunohistochemical analysis of eGFP revealed that POMC is primarily localized within the caudal NTS. Neurochemical analysis indicated that POMCNTS is not co-expressed with tyrosine hydroxylase (TH), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), brain-derived neurotrophic factor (BDNF), nesfatin, nitric oxide synthase 1 (nNOS), seipin, or choline acetyltransferase (ChAT) cells, whereas 100% of POMCNTS is co-expressed with transcription factor paired-like homeobox2b (Phox2b). We observed that 20% of POMCNTS cells express receptors for adipocyte hormone leptin (LepRbs) using a PomceGFP:LepRbCre:tdTOM double-reporter line. Elevations in endogenous or exogenous leptin levels increased the in vivo activity (c-FOS) of a small subset of POMCNTS cells. Using ex vivo slice electrophysiology, we observed that this effect of leptin on POMCNTS cell activity is postsynaptic. These findings reveal that a subset of POMCNTS cells are responsive to both changes in energy status and the adipocyte hormone leptin, findings of relevance to the neurobiology of obesity.
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PMID:Neurochemical Characterization of Brainstem Pro-Opiomelanocortin Cells. 3216 24