PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-19 (19)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
1.  An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy 
Nature genetics  2013;45(8):947-950.
DNA polymerase delta, whose catalytic subunit is encoded by POLD1, is responsible for lagging strand DNA synthesis during DNA replication1. It achieves this with high fidelity due to its intrinsic 3′ to 5′ exonuclease activity, which confers proofreading ability. Missense mutations in the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancer2. Here we report a recurring heterozygous single amino acid deletion at the polymerase active site of POLD1 that abolishes DNA polymerase activity but only mildly impairs 3′ to 5′ exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This suggests that perturbation of function of the ubiquitously expressed POLD1 polymerase has surprisingly tissue-specific effects in man, and argues for an important role for POLD1 function in adipose tissue homeostasis.
doi:10.1038/ng.2670
PMCID: PMC3785143  PMID: 23770608
2.  Intrahepatic Lipid Content and Insulin Resistance Are More Strongly Associated with Impaired NEFA Suppression after Oral Glucose Loading Than with Fasting NEFA Levels in Healthy Older Individuals 
Introduction. The mechanisms underlying the association between insulin resistance and intrahepatic lipid (IHL) accumulation are not completely understood. We sought to determine whether this association was explained by differences in fasting non-esterified fatty acid (NEFA) levels and/or NEFA suppression after oral glucose loading. Materials and Methods. We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin, and NEFA levels measured over two hours. IHL was quantified with magnetic resonance spectroscopy. Insulin sensitivity was measured with the oral glucose insulin sensitivity (OGIS) model, the leptin: adiponectin ratio (LAR), and the homeostasis model assessment (HOMA). Results. Measures of insulin sensitivity were not associated with fasting NEFA levels, but OGIS was strongly associated with NEFA suppression at 30 minutes and strongly inversely associated with IHL. Moreover, LAR was strongly inversely associated with NEFA suppression and strongly associated with IHL. This latter association (beta = 1.11 [1.01, 1.21], P = 0.026) was explained by reduced NEFA suppression (P = 0.24 after adjustment). Conclusions. Impaired postprandial NEFA suppression, but not fasting NEFA, contributes to the strong and well-established association between whole body insulin resistance and liver fat accumulation.
doi:10.1155/2013/870487
PMCID: PMC3659510  PMID: 23737780
3.  Mitochondrial Oxidative Phosphorylation Is Impaired in Patients with Congenital Lipodystrophy 
Objective:
Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle.
Research Design and Methods:
Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls.
Results:
The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P < 0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates.
Conclusions:
Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.
doi:10.1210/jc.2011-2587
PMCID: PMC3380089  PMID: 22238385
4.  Human Frame Shift Mutations Affecting the Carboxyl Terminus of Perilipin Increase Lipolysis by Failing to Sequester the Adipose Triglyceride Lipase (ATGL) Coactivator AB-hydrolase-containing 5 (ABHD5)* 
The Journal of Biological Chemistry  2011;286(40):34998-35006.
Perilipin (PLIN1) is a constitutive adipocyte lipid droplet coat protein. N-terminal amphipathic helices and central hydrophobic stretches are thought to anchor it on the lipid droplet, where it appears to function as a scaffold protein regulating lipase activity. We recently identified two different C-terminal PLIN1 frame shift mutations (Leu-404fs and Val-398fs) in patients with a novel subtype of partial lipodystrophy, hypertriglyceridemia, severe insulin resistance, and type 2 diabetes (Gandotra, S., Le Dour, C., Bottomley, W., Cervera, P., Giral, P., Reznik, Y., Charpentier, G., Auclair, M., Delépine, M., Barroso, I., Semple, R. K., Lathrop, M., Lascols, O., Capeau, J., O'Rahilly, S., Magré, J., Savage, D. B., and Vigouroux, C. (2011) N. Engl. J. Med. 364, 740–748.) When overexpressed in preadipocytes, both mutants fail to inhibit basal lipolysis. Here we used bimolecular fluorescence complementation assays to show that the mutants fail to bind ABHD5, permitting its constitutive coactivation of ATGL, resulting in increased basal lipolysis. siRNA-mediated knockdown of either ABHD5 or ATGL expression in the stably transfected cells expressing mutant PLIN1 reduced basal lipolysis. These insights from naturally occurring human variants suggest that the C terminus sequesters ABHD5 and thus inhibits basal ATGL activity. The data also suggest that pharmacological inhibition of ATGL could have therapeutic potential in patients with this rare but metabolically serious disorder.
doi:10.1074/jbc.M111.278853
PMCID: PMC3186430  PMID: 21757733
Cell Biology; Lipase; Lipid Droplets; Lipid Metabolism; Lipodystrophy
5.  Mitochondrial dysfunction in patients with primary congenital insulin resistance 
The Journal of Clinical Investigation  2011;121(6):2457-2461.
Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.
doi:10.1172/JCI46405
PMCID: PMC3104774  PMID: 21555852
6.  Early Diagnosis of Werner's Syndrome Using Exome-Wide Sequencing in a Single, Atypical Patient 
Genetic diagnosis of inherited metabolic disease is conventionally achieved through syndrome recognition and targeted gene sequencing, but many patients receive no specific diagnosis. Next-generation sequencing allied to capture of expressed sequences from genomic DNA now offers a powerful new diagnostic approach. Barriers to routine diagnostic use include cost, and the complexity of interpreting results arising from simultaneous identification of large numbers of variants. We applied exome-wide sequencing to an individual, 16-year-old daughter of consanguineous parents with a novel syndrome of short stature, severe insulin resistance, ptosis, and microcephaly. Pulldown of expressed sequences from genomic DNA followed by massively parallel sequencing was undertaken. Single nucleotide variants were called using SAMtools prior to filtering based on sequence quality and existence in control genomes and exomes. Of 485 genetic variants predicted to alter protein sequence and absent from control data, 24 were homozygous in the patient. One mutation – the p.Arg732X mutation in the WRN gene – has previously been reported in Werner's syndrome (WS). On re-evaluation of the patient several early features of WS were detected including loss of fat from the extremities and frontal hair thinning. Lymphoblastoid cells from the proband exhibited a defective decatenation checkpoint, consistent with loss of WRN activity. We have thus diagnosed WS some 15 years earlier than average, permitting aggressive prophylactic therapy and screening for WS complications, illustrating the potential of exome-wide sequencing to achieve early diagnosis and change management of rare autosomal recessive disease, even in individual patients of consanguineous parentage with apparently novel syndromes.
doi:10.3389/fendo.2011.00008
PMCID: PMC3356119  PMID: 22654791
Werner's syndrome; whole exome sequencing; insulin resistance; diabetes; WRN
7.  Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance 
Physiological reviews  2007;87(2):507-520.
Contextual setting
Although abnormal glucose metabolism defines type 2 diabetes and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of type 2 diabetes are increasingly focussed on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid-/ lipid metabolism and insulin resistance. As “Mouse Models of Insulin Resistance” were comprehensively reviewed in Physiological Reviews by Nandi et al in 2004 (67), we will concentrate on human studies involving the use of isotopes and/ or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight.
doi:10.1152/physrev.00024.2006
PMCID: PMC2995548  PMID: 17429039
8.  Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia 
The Journal of Clinical Investigation  2010;120(4):1345-1354.
Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor β (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor α sensitivity to elevated thyroid hormone levels.
doi:10.1172/JCI38793
PMCID: PMC2846038  PMID: 20237409
9.  Randomized controlled trial of the efficacy of aerobic exercise in reducing metabolic risk in healthy older people: The Hertfordshire Physical Activity Trial 
Background
While there are compelling observational data confirming that individuals who exercise are healthier, the efficacy of aerobic exercise interventions to reduce metabolic risk and improve insulin sensitivity in older people has not been fully elucidated. Furthermore, while low birth weight has been shown to predict adverse health outcomes later in life, its influence on the response to aerobic exercise is unknown. Our primary objective is to assess the efficacy of a fully supervised twelve week aerobic exercise intervention in reducing clustered metabolic risk in healthy older adults. A secondary objective is to determine the influence of low birth weight on the response to exercise in this group.
Methods/Design
We aim to recruit 100 participants born between 1931–1939, from the Hertfordshire Cohort Study and randomly assign them to no intervention or to 36 fully supervised one hour sessions on a cycle ergometer, over twelve weeks. Each participant will undergo detailed anthropometric and metabolic assessment pre- and post-intervention, including muscle biopsy, magnetic resonance imaging and spectroscopy, objective measurement of physical activity and sub-maximal fitness testing.
Discussion
Given the extensive phenotypic characterization, this study will provide valuable insights into the mechanisms underlying the beneficial effects of aerobic exercise as well as the efficacy, feasibility and safety of such interventions in this age group.
Trial Registration
Current Controlled Trials: ISRCTN60986572
doi:10.1186/1472-6823-9-15
PMCID: PMC2708167  PMID: 19545359
10.  TCF7L2 Polymorphisms Modulate Proinsulin Levels and β-Cell Function in a British Europid Population 
Diabetes  2007;56(7):1943-1947.
Rapidly accumulating evidence shows that common T-cell transcription factor (TCF)7L2 polymorphisms confer risk of type 2 diabetes through unknown mechanisms. We examined the association between four TCF7L2 single nucleotide polymorphisms (SNPs), including rs7903146, and measures of insulin sensitivity and insulin secretion in 1,697 Europid men and women of the population-based MRC (Medical Research Council)-Ely study. The T-(minor) allele of rs7903146 was strongly and positively associated with fasting proinsulin (P = 4.55 × 10−9) and 32,33 split proinsulin (P = 1.72 × 10−4) relative to total insulin levels; i.e., differences between T/T and C/C homozygotes amounted to 21.9 and 18.4% respectively. Notably, the insulin-to-glucose ratio (IGR) at 30-min oral glucose tolerance test (OGTT), a frequently used surrogate of first-phase insulin secretion, was not associated with the TCF7L2 SNP (P > 0.7). However, the insulin response (IGR) at 60-min OGTT was significantly lower in T-allele carriers (P = 3.5 × 10−3). The T-allele was also associated with higher A1C concentrations (P = 1.2 × 10−2) and reduced β-cell function, assessed by homeostasis model assessment of β-cell function (P = 2.8 × 10−2). Similar results were obtained for the other TCF7L2 SNPs. Of note, both major genes involved in proinsulin processing (PC1, PC2) contain TCF-binding sites in their promoters. Our findings suggest that the TCF7L2 risk allele may predispose to type 2 diabetes by impairing β-cell proinsulin processing. The risk allele increases proinsulin levels and diminishes the 60-min but not 30-min insulin response during OGTT. The strong association between the TCF7L2 risk allele and fasting proinsulin but not insulin levels is notable, as, in this unselected and largely normoglycemic population, external influences on β-cell stress are unlikely to be major factors influencing the efficiency of proinsulin processing.
doi:10.2337/db07-0055
PMCID: PMC2668957  PMID: 17416797
11.  Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis 
Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.
doi:10.1172/JCI37432
PMCID: PMC2631303  PMID: 19164855
13.  A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice 
PLoS Medicine  2008;5(1):e27.
Background
Stored glycogen is an important source of energy for skeletal muscle. Human genetic disorders primarily affecting skeletal muscle glycogen turnover are well-recognised, but rare. We previously reported that a frameshift/premature stop mutation in PPP1R3A, the gene encoding RGL, a key regulator of muscle glycogen metabolism, was present in 1.36% of participants from a population of white individuals in the UK. However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant.
Methods and Findings
In this study we found a similar prevalence of the variant in an independent UK white population of 744 participants (1.46%) and, using in vivo 13C magnetic resonance spectroscopy studies, demonstrate that human carriers (n = 6) of the variant have low basal (65% lower, p = 0.002) and postprandial muscle glycogen levels. Mice engineered to express the equivalent mutation had similarly decreased muscle glycogen levels (40% lower in heterozygous knock-in mice, p < 0.05). In muscle tissue from these mice, failure of the truncated mutant to bind glycogen and colocalize with glycogen synthase (GS) decreased GS and increased glycogen phosphorylase activity states, which account for the decreased glycogen content.
Conclusions
Thus, PPP1R3A C1984ΔAG (stop codon 668) is, to our knowledge, the first prevalent mutation described that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle. The fact that it is present in ∼1 in 70 UK whites increases the potential biomedical relevance of these observations.
Stephen O'Rahilly and colleagues describe the effect of a mutation inPPP1R3A, present in 1.36% of participants from one UK population, that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle.
Editors' Summary
Background.
The human body gets the energy it needs for day-to-day living from food in a process called metabolism. However, not all the energy released by metabolism is used immediately. Some is stored in skeletal muscles as glycogen, a glucose polymer that is used during high intensity exercise. After eating, chemicals in the digestive system release glucose (a type of sugar) from food into the bloodstream where it triggers insulin release from the pancreas. Insulin instructs muscle, liver and fat cells to remove glucose from the bloodstream to keep the amount of sugar in the blood at a safe level. The cells use the glucose immediately as fuel or convert it into glycogen or fat for storage. Glycogen turnover (the depletion and replacement of glycogen stores) is tightly controlled by glycogen synthase and glycogen phosphorylase, enzymes that make and destroy glycogen, respectively. A third enzyme called protein phosphatase 1 promotes net glycogen synthesis by activating glycogen synthase and inactivating glycogen phosphorylase. The activity of protein phosphatase 1 is regulated by a family of “targeting subunits.” In muscle, one of these targeting subunits, called RGL, facilitates protein phosphatase 1 action on glycogen synthase and glycogen phosphorylase.
Why Was This Study Done?
Several known human genetic disorders affect the breakdown of muscle glycogen but few genetic changes (mutations) have been found that decrease the synthesis of muscle glycogen. Researchers are interested in discovering mutations that affect glycogen turnover and other aspects of metabolism because some of these may be involved in the development of diabetes, an important metabolic disorder characterized by high blood sugar levels. In this study, the researchers have investigated how a recently identified mutation in PPP1R3A, the gene that encodes RGL, affects glycogen synthesis. This mutation—PPP1R3A FS—was previously found in 1.36% of a UK white population. It causes the production of a short version of RGL that lacks the part of the molecule that tethers RGL to a cellular structure called the sarcoplasmic reticulum but leaves its glycogen binding domain intact.
What Did the Researchers Do and Find?
To confirm that PPP1R3A FS is a common mutation in the UK white population, the researchers sequenced the gene in 744 healthy adults enrolled in the Oxford Biobank (which hopes to uncover metabolically important genetic variations by monitoring the health of a large number of 30- to 50-year-old people from whom DNA has been collected). 1.46% of these people had the PPP1R3A FS mutation. To examine glycogen storage in carriers of the mutation, the researchers used a technique called in vivo 13C magnetic resonance spectroscopy. Basal muscle glycogen levels and those reached after a meal were lower in these individuals than in people without the mutation but their blood sugar and insulin levels were normal. Finally, to examine how the mutation reduces muscle glycogen, the researchers made mice carrying the PPP1R3A FS mutation. Like the human carriers, these mice had less glycogen than normal in their muscles. Unexpectedly, in biochemical experiments the truncated RGL protein made by the mutant mice did not bind to glycogen or co-localize with glycogen synthase. This lack of binding decreased the activity of glycogen synthase and increased the activity of glycogen phosphorylase, thus decreasing muscle glycogen.
What Do These Findings Mean?
These findings identify the PPP1R3A FS mutation as the first prevalent mutation known to impair glycogen synthesis and to decrease glycogen levels in human skeletal muscles. They also confirm that this mutation is very common in UK whites. Although these human carriers do not report any exercise intolerance, detailed studies are needed to test whether the mutation has any effect on skeletal muscle performance. In addition, suggest the researchers, the mutation might be involved in the development of type 2 diabetes. Impaired insulin-stimulated glycogen synthesis, which is a feature of insulin-resistant muscle and liver cells, is thought to be a key event in the development of type 2 diabetes. Although some previous results indicate that the PPP1R3A FS mutations can sometimes predispose people to develop insulin resistance, only a large population-based study in multiple ethnic groups will reveal whether the PPP1R3A FS mutation has an important impact on the development of type 2 diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050027.
Wikipedia has pages on metabolism and on glycogen (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The MedlinePlus encyclopedia provides information about diabetes (in English and Spanish)
The UK Biobank is looking for genetic variations among human populations that are associated with metabolic and other disorders
Web sites are available with brief descriptions of the research programs of Stephen O'Rahilly and Anna DePaoli-Roach
doi:10.1371/journal.pmed.0050027
PMCID: PMC2214798  PMID: 18232732
14.  Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 
Journal of Clinical Investigation  2006;116(3):817-824.
Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
doi:10.1172/JCI27300
PMCID: PMC1366503  PMID: 16485039
15.  Perilipin Deficiency and Autosomal Dominant Partial Lipodystrophy 
The New England journal of medicine  2011;364(8):740-748.
Summary
Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.
doi:10.1056/NEJMoa1007487
PMCID: PMC3773916  PMID: 21345103
16.  Mosaic Overgrowth with Fibroadipose Hyperplasia is Caused by Somatic Activating Mutations in PIK3CA 
Nature genetics  2012;44(8):928-933.
The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2, or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells of a patient with an unclassified syndrome of congenital, progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated p.His1047Leu mutation in PIK3CA, which encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in 10 further patients with overlapping syndromes identified either p.His1047Leu or a second cancer-associated mutation, p.His1047Arg, in 9 cases. Affected dermal fibroblasts showed enhanced basal and EGF-stimulated phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation and concomitant activation of downstream signaling. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.
doi:10.1038/ng.2332
PMCID: PMC3461408  PMID: 22729222
17.  Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC 
EMBO molecular medicine  2009;1(5):280-287.
Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as, like obesity, they typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. Here we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes who was found to be homozygous for a premature truncation mutation in the lipid droplet protein CIDEC (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. As well as describing a novel autosomal recessive form of familial partial lipodystrophy these observations suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
doi:10.1002/emmm.200900037
PMCID: PMC2891108  PMID: 20049731
lipodystrophy; insulin resistance; lipid droplet; CIDEC (Fsp27)
18.  Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC 
EMBO Molecular Medicine  2009;1(5):280-287.
Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
doi:10.1002/emmm.200900037
PMCID: PMC2891108  PMID: 20049731
lipodystrophy; insulin resistance; lipid droplet; CIDEC (Fsp27)
19.  Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC 
EMBO Molecular Medicine  2009;1(5):280-287.
Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
doi:10.1002/emmm.200900037
PMCID: PMC2891108  PMID: 20049731
lipodystrophy; insulin resistance; lipid droplet; CIDEC (Fsp27)

Results 1-19 (19)