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Biomedical subjects

Abhimanyu Garg

Publications and source records attributed to Abhimanyu Garg.

At least 19 recordsLinked to original sources
PubMed2006

Review: long-term impact of bariatric surgery on body weight, comorbidities, and nutritional status.

CONTEXT: The number of patients who undergo Roux-en-Y gastric bypass (RYGB) and gastric banding (GB) surgeries has increased dramatically over the past decade, yet the long-term impact of these surgeries on body weight, comorbidities, and nutritional status remains unclear, as do the mechanisms of weight regain. EVIDENCE ACQUISITION: The articles were found via PubMed searches. To review the impact of bariatric surgery on weight maintenance and comorbidities, only articles with a postoperative follow-up of 3 yr or longer were included. The articles on nutritional status had a follow-up of 12 months or longer. CONCLUSIONS: RYGB and GB surgeries lead to substantial weight loss in individuals with morbid obesity. However, significant weight regain occurs over the long term, and according to the only well-designed prospective controlled study, the improvement in comorbidities associated with weight loss mitigates in the long term on weight regain. There is some evidence from a retrospective study that RYGB surgery is associated with a modest decrease in long-term mortality. These results remain to be substantiated by well-designed, long-term, randomized and prospective controlled studies. The mechanisms that lead to weight regain need to be further examined and may include increase in energy intake due to enlargement of stoma and adaptive changes in the levels of gut and adipocyte hormones such as ghrelin and leptin, which regulate energy intake; decrease in physical activity; changes in energy expenditure; and other factors. In addition to weight regain, RYGB surgery is associated with frequent incidence of iron, vitamin B12, folate, calcium, and vitamin D deficiency, which requires regular supplementation and monitoring.

Bariatric Surgery↗
PubMed2006

Functional characterization of human 1-acylglycerol-3-phosphate acyltransferase isoform 8: cloning, tissue distribution, gene structure, and enzymatic activity.

Glycerophospholipids and triglycerides are synthesized de novo by cells through an evolutionary conserved process involving serial acylations of phosphorylated glycerol. Various isoforms of the enzyme, 1-acylglycerol-3-phosphate acyltransferase (AGPAT), acylate lysophosphatidic acid at the sn-2 position to produce phosphatidic acid. We cloned a cDNA predicted to be AGPAT isoform and designated it AGPAT8. Human and mouse AGPAT8 proteins are 89% homologous, and their gene structure is also highly conserved. AGPAT8 is most closely related to AGPAT5, and its cDNA is expressed most in the heart, while AGPAT5 is expressed more in the prostate and testis. In cell lysates, AGPAT8 shows moderate acyltransferase activity with [(3)H]oleoyl-CoA but lacks acyl-CoA:lysocardiolipin acyltransferase activity. In whole cells upon incubation with [(14)C]linoleic acid, most of the radioactivity was recovered in phosphatidyl ethanolamine, phosphatidyl choline and phosphatidic acid fraction. Of the two well conserved acyltransferase motifs, NHX(4)D is present in AGPAT8, whereas arginine in the EGTR motif is substituted by aspartate. However, mutation of EGTD to EGTR did not increase enzymatic activity significantly. Based on the X-ray crystallographic structure of a related acyltransferase, squash gpat, a model is proposed in which a hydrophobic pocket in AGPAT8 accommodates fatty acyl chains of both substrates in an orientation where the NHX(4)D motif participates in catalysis.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2006

Adipose tissue dysfunction in obesity and lipodystrophy.

The primary function of adipose tissue is to store energy in the form of triglycerides during periods of energy excess and to release the energy during fasting or starvation as free fatty acids and glycerol. Adipose tissue secretes a variety of peptides called adipocytokines (eg, leptin, adiponectin, tumor necrosis factor-alpha, interleukin-6, resistin, visfatin) that have endocrine, autocrine, and paracrine effects on the brain, liver, and skeletal muscles. These peptides play an important role in the regulation of energy homeostasis and intermediary metabolism. Adipose tissue also aromatizes androgens to estrogens, and some adipose tissue depots (mechanical fat) serve a protective or cushioning function. Dysfunction of adipose tissue can result in insulin resistance and its metabolic complications in patients with excess body fat (obesity) or markedly reduced body fat (lipodystrophy). Alterations in free fatty acid and adipocytokine release from adipose tissue may underlie metabolic complications.

Adipose Tissue↗
PubMed2006

Lipodystrophy: lessons in lipid and energy metabolism.

PURPOSE OF REVIEW: Lipodystrophies are rare inherited and acquired disorders characterized by the selective loss of adipose tissue. Despite marked phenotypic and genotypic heterogeneity, most lipodystrophic syndromes predispose to similar metabolic complications seen in patients with obesity, such as insulin resistance, diabetes mellitus, hepatic steatosis and dyslipidemia. The purpose of this review is to highlight the current understanding of the mechanisms underlying dyslipidemia in patients with lipodystrophies. RECENT FINDINGS: Marked hypertriglyceridemia and reduced levels of high-density lipoprotein cholesterol are commonly seen, and the severity of these metabolic abnormalities seems to be related to the extent of fat loss. The precise mechanisms by which the lack of adipose tissue causes hypertriglyceridemia remain unknown. Anecdotal kinetic studies in hyperglycemic patients with lipodystrophies have revealed accelerated lipolysis and increased free fatty acid turnover, which drives hepatic triglyceride and very low-density lipoprotein synthesis. Other mechanisms may also be involved in causing dyslipidemia and ectopic triglyceride accumulation in the liver and skeletal muscles that remain to be identified. SUMMARY: Understanding the pathophysiology of dyslipidemia in these rare disorders of lipodystrophies may offer insights into the normal role of adipocytes in maintaining metabolic homeostasis, and its disturbances in common forms of obesity.

Adipose Tissue↗
PubMed2006

Genetic disorders of adipose tissue development, differentiation, and death.

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.

Adipose Tissue↗
PubMed2006

Genetic basis of lipodystrophies and management of metabolic complications.

Selective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPARgamma), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2006

Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency.

BACKGROUND: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by skeletal abnormalities such as hypoplasia of the mandible and clavicles and acro-osteolysis. Other features include cutaneous atrophy and lipodystrophy. Two genetic loci are known for MAD: lamin A/C (LMNA), encoding structural nuclear lamina proteins, and zinc metalloproteinase (ZMPSTE24), a membrane-bound endoprotease involved in post-translational proteolytic cleavage of carboxy terminal residues of prelamin A to form mature lamin A. METHODS: Mutational analysis of ZMPSTE24 in an additional patient with MAD and determination of functional activity of mutant ZMPSTE24 in a yeast growth arrest pheromone diffusion (halo) assay. RESULTS: We previously reported a Belgian woman with MAD who had ZMPSTE24 mutations and died of complications of chronic renal failure at the age of 27.5 years. We now report a 37-year-old Australian man with MAD who also had compound heterozygous mutations in the ZMPSTE24 gene, a null mutation, Phe361fsX379, and a missense mutation, Asn265Ser, which is partially active in the yeast complementation assay. He also developed end-stage renal disease and, despite receiving a cadaveric renal transplantation, died prematurely at the age of 37 years. Renal biopsies of both patients revealed focal segmental glomerulosclerosis, and the female patient had the collapsing variant. CONCLUSION: These observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency.

Acro-Osteolysis↗
PubMed2005

Laminopathies: multisystem dystrophy syndromes.

Laminopathies are a heterogeneous group of genetic disorders due to abnormalities in type A lamins and can manifest varied clinical features affecting many organs including the skeletal and cardiac muscle, adipose tissue, nervous system, cutaneous tissue, and bone. Mutations in the gene encoding lamins A and C (LMNA) cause primary laminopathies, including various types of lipodystrophies, muscular dystrophies and progeroid syndromes, mandibuloacral dysplasia, dilated cardiomyopathies, and restrictive dermopathy. The secondary laminopathies are due to mutations in ZMPSTE24 gene which encodes for a zinc metalloproteinase involved in processing of prelamin A into mature lamin A and cause mandibuloacral dysplasia and restrictive dermopathy. Skin fibroblast cells from many patients with laminopathies show a range of abnormal nuclear morphology including bleb formation, honeycombing, and presence of multi-lobulated nuclei. The mechanisms by which mutations in LMNA gene cause multisystem dystrophy are an active area of current investigation. Further studies are needed to understand the underlying mechanisms of marked pleiotropy in laminopathies.

Cardiomyopathy, Dilated↗
PubMed2005

A homozygous mutation in the lamin A/C gene associated with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features.

CONTEXT: Mutations in the lamin A/C (LMNA) gene have been reported in a wide variety of disorders, including lipodystrophies, cardiomyopathy, muscular dystrophies, neuropathy, mandibuloacral dysplasia, restrictive dermopathy, and progeria. OBJECTIVE: The objective of this study was to carry out mutational analysis of LMNA in a patient with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features. DESIGN: The study design was a descriptive case report. SETTING: The study was performed at a referral center. PATIENT: A 44-yr-old male of European descent with an autosomal recessive arthropathy syndrome affecting predominantly the distal femora and proximal tibia in the knee with tendinous calcifications was studied. He also had progeroid features, such as pinched nose and micrognathia, cataract, alopecia, generalized lipodystrophy, and sclerodermatous skin. MAIN OUTCOME MEASURES: The main outcome measures were mutational analysis of lamin A/C (LMNA) and its processing enzyme, zinc metalloproteinase (ZMPSTE24), as candidate genes. RESULTS: We found a homozygous nucleotide substitution, 1718C>T, in exon 11 of the LMNA gene, resulting in substitution of a well-conserved residue serine at position 573 with leucine (S573L). This missense mutation only affects lamin A, not lamin C, because the alternative splicing site is located in exon 10. Immunofluorescence staining of the nuclei from his skin fibroblasts showed occasional misshapen morphology. CONCLUSIONS: The S573L homozygous LMNA mutation is associated with a novel phenotype of arthropathy, tendinous calcifications, and progeroid features distinct from the acroosteolysis previously reported in patients with mandibuloacral dysplasia caused by LMNA or ZMPSTE24 mutations. Thus, arthropathy with tendinous calcifications can be added to the growing list of disorders associated with LMNA mutations.

Adult↗
PubMed2005

Phenotypic heterogeneity in body fat distribution in patients with atypical Werner's syndrome due to heterozygous Arg133Leu lamin A/C mutation.

CONTEXT: A heterozygous missense mutation substituting arginine at position 133 to leucine in the lamin A/C protein has been reported in two young women with clinical features of short stature, bird-like faces, and early onset of aging processes. OBJECTIVE: The objective of the study was to carry out detailed phenotyping of these two women by evaluating the pattern of fat loss using anthropometry, dual-energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI) and study metabolic abnormalities in glucose and lipid metabolism. DESIGN: The study consisted of descriptive case reports. SETTING: The study was conducted at a referral center. PATIENTS: Patient 1 was a 23-yr-old African-American female with progeroid features. Patient 2 was a 24-yr-old Caucasian female with generalized lipodystrophy, hypertriglyceridemia, and severe insulin resistance diabetes who required more than 200 U of insulin daily. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Body fat distribution to characterize pattern of lipodystrophy and nuclear morphology abnormalities in skin fibroblasts were studied. RESULTS: Patient 1 had normal body fat (27%) by DEXA. However, MRI revealed relative paucity of sc fat in the distal extremities, with preservation of sc truncal fat. She had impaired glucose tolerance and elevated postprandial serum insulin levels. Patient 2, in contrast, had only 11.6% body fat as determined by DEXA and had generalized loss of sc and intraabdominal fat on MRI. Skin fibroblasts from patient 2 showed marked abnormal nuclear morphology, compared with those from patient 1. Despite the deranged nuclear morphology, the lamin A/C remained localized to the nuclear envelope, and the nuclear DNA remained within the nucleus. CONCLUSIONS: Atypical Werner's syndrome associated with Arg133Leu mutation in the LMNA gene presents with a phenotypically heterogeneous disorder. Furthermore, the severity of metabolic complications seems to correlate with the extent of lipodystrophy.

Adipose Tissue↗
PubMed2005

A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia.

CONTEXT: Mandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, lipodystrophy, and mottled cutaneous pigmentation. MAD patients with type A lipodystrophy with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions have been previously reported to carry a homozygous Arg527His mutation in LMNA (Lamin A/C) gene. Among those with type B pattern of lipodystrophy with generalized loss of sc fat, we recently reported a patient carrying compound heterozygous mutations in an endoprotease, zinc metalloproteinase (ZMPSTE24), gene that is involved in posttranslational processing of prelamin A to mature lamin A. OBJECTIVE: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy. DESIGN AND SETTING: We studied descriptive case reports at a referral center. PATIENTS: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey. MAIN OUTCOME MEASURES: We assessed genotype-phenotype relationships. RESULTS: We now report that both these patients have a novel homozygous missense mutation (c.1586C-->T; c refers to cDNA reference sequence) in LMNA that replaces a well-conserved residue alanine at position 529 to valine. Intragenic single-nucleotide polymorphisms revealed a common haplotype spanning 2.5 kb around the mutated nucleotide in the parents of both the affected subjects, suggesting ancestral origin of the mutation. The female patient had no breast development despite normal menstruation, a phenotype different from that seen in women with MAD and Arg527His LMNA mutation. CONCLUSIONS: We conclude that two homozygous missense LMNA mutations involving the arginine 527 and alanine 529 residues cause MAD with subtle variations in phenotype.

Abnormalities, Multiple↗
PubMed2005

Enzymatic activity of naturally occurring 1-acylglycerol-3-phosphate-O-acyltransferase 2 mutants associated with congenital generalized lipodystrophy.

Mutations in the gene encoding 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) have been reported in patients with congenital generalized lipodystrophy (CGL). AGPAT2, a 278 amino acid protein, belongs to the acyltransferase enzyme family, and has two conserved motifs, NHX(4)D and EGTR, involved in the enzymatic activity. The AGPATs catalyze acylation of lysophosphatidic acid (LPA) to phosphatidic acid (PA) during the biosynthesis of glycerophospholipids and triglycerides from glycerol-3-phosphate. The present studies were designed to determine the enzymatic activity of AGPAT2 mutants found in CGL patients to provide a molecular explanation for the phenotype and to obtain additional information about the structure-function relationship of AGPAT2 protein. The enzymatic activities of the wild type AGPAT2 and mutants were determined in cell lysates of overexpressing Chinese hamster ovary cells by measuring the conversion of [(3)H]LPA to [(3)H]PA in the presence of oleoyl-coenzyme A. Whereas, the R68X, 221delGT, 252delMRT, D180fsX251, and V167fsX183 mutants had markedly reduced enzymatic activity (median <15% of the wild type), the mutants, 140delF, G136R, and L228P, retained median activity ranging from 15% to 40% of the wild type enzyme. However, the missense mutant, A239V, had 90% of the wild type activity. We suggest that reduction in AGPAT2 enzymatic activity underlies the loss of adipose tissue in CGL. Our observations reveal an important role of various carboxy-terminal residues in determining the enzymatic activity of AGPAT2.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2005

Regional body fat distribution in HIV-infected patients with lipodystrophy.

BACKGROUND: Objective criteria for the assessment of patients with lipodystrophy syndrome in human immunodeficiency virus infection (LDHIV) have not emerged. METHODS: We compared regional body fat changes in 13 men with severe LDHIV on protease inhibitor-inclusive antiretroviral therapy with 13 control HIV-infected men using anthropometry, dual-energy X-ray absorptiometry (DEXA), and whole-body magnetic resonance imaging (MRI). RESULTS: LDHIV patients, compared with control subjects, had thinner gluteal, suprailiac, and triceps skinfolds (p < .01) and increased waist circumference (98 +/- 5 cm vs 86 +/- 9 cm, respectively; p = .0008). DEXA studies revealed reduced lower extremity fat (12 +/- 5% vs 22 +/- 9%; p = .0006), increased head and neck fat (18 +/- 3% vs 16 +/- 1%; p = .01), and increased proportion of total body fat in the trunk (65 +/- 7% vs 53 +/- 8%; p = .0005). MRI analysis revealed reduced thigh fat (12 +/- 5% vs 22 +/- 12%; p = .01), increased dorsocervical fat depth (47 +/- 24 mm vs 19 +/- 7 mm; p = .0009), and nearly significant increase in intra-abdominal fat (218 +/- 90 cm2 vs 157 +/- 70 cm2; p = .057). Interestingly, control subjects showed a positive relationship between intra-abdominal and dorsocervical fat (r= .57, p = .04), but the LDHIV patients showed a negative relationship (r= -.55, p = .05), suggesting a novel split phenotype among LDHIV patients of either dorsocervical or intra-abdominal fat accumulation. CONCLUSIONS: We conclude that MRI provides the best tools for definition of LDHIV syndrome and reveals variable phenotypes among LDHIV patients.

Absorptiometry, Photon↗
PubMed2005

Effect of a high-carbohydrate versus a high--cis-monounsaturated fat diet on blood pressure in patients with type 2 diabetes.

OBJECTIVE: To investigate whether blood pressure is different in type 2 diabetic patients on a diet rich in carbohydrates versus a diet rich in cis-monounsaturated fatty acids. Data on the dietary effects on these diets' glucose and lipid metabolism have been previously published. RESEARCH DESIGN AND METHODS: The study compared the effect of feeding 42 type 2 diabetic patients a carefully controlled isoenergic high-carbohydrate (high-carb; 55% energy as carbohydrate, 30% as fat, and 10% as monounsaturated fat) and high-monounsaturated fat (high-mono; 45% energy as fat, 25% as monounsaturated fat, and 40% as carbohydrate) diet for 6 weeks each in a four-center, randomized, cross-over study on blood pressure. Twenty-one patients continued the diet they received during the second phase for an additional 8 weeks. RESULTS: According to repeated-measures ANOVA, blood pressure during the last 3 days of each phase was similar after 6 weeks of the high-carb and high-mono diets (systolic blood pressure: 128 +/- 16 vs. 127 +/- 15 mmHg, P = 0.9; diastolic blood pressure: 75 +/- 7 vs. 75 +/- 8 mmHg, P = 0.7). However, after 14 weeks of the high-carb diet (n = 13), there was a significant increase in blood pressure compared with 6 weeks of the high-mono diet (systolic blood pressure: 132 +/- 13 vs. 126 +/- 11 mmHg, P = 0.04; diastolic blood pressure: 83 +/- 6 vs. 76 +/- 7 mmHg, P = 0.002). After 14 weeks of the high-mono diet (n = 8), the reduction in blood pressure was not significant compared with 6 weeks of the high-carb diet (systolic blood pressure: 118 +/- 14 vs. 121 +/- 16 mmHg, P = 0.4; diastolic blood pressure: 71 +/- 8 vs. 75 +/- 10 mmHg, P = 0.3). CONCLUSION: Although the exchange of carbohydrates with monounsaturated fats may not affect blood pressure in the short term, long-term consumption of a high-carbohydrate diet may modestly raise blood pressure in type 2 diabetic patients.

Aged↗
PubMed2004

Adipocyte biology and adipocytokines.

Adipose tissue actively participates in regulation of food intake, energy expenditure, fuel metabolism, and a variety of other physiologic processes through its endocrine, paracrine, and autocrine secretory products (Table 4). Abnormal synthesis of these secretory products may be related to the pathogenesis of insulin resistance and its complications in patients who have adipose tissue disorders, such as obesity and lipodvstrophies.

Adipocytes↗
PubMed2004

Lipodystrophies: rare disorders causing metabolic syndrome.

Recent advances in the understanding of the molecular basis of genetic lipodystrophies have promoted understanding of how adipose tissue disorders can cause the metabolic syndrome and its complications. These discoveries hold promise for elucidating pathways and mechanisms by which common disorders of obesity cause metabolic complications. Novel therapeutic approaches for patients with lipodystrophies also may have implications for treatment of the metabolic syndrome in patients with regional adiposity. This article reviews these recent advances in our knowledge of the clinical features, metabolic abnormalities, and pathogenetic or other bases of various types of lipodystrophies.

Humans↗