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Wu CJ, Liu H, Tu LJ, Hu JY. Peroxisome proliferator-activated receptor gamma mutation in familial partial lipodystrophy type three: A case report and review of literature. World J Diabetes 2024; 15:2360-2369. [PMID: 39676812 PMCID: PMC11580599 DOI: 10.4239/wjd.v15.i12.2360] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 09/22/2024] [Accepted: 10/23/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND Familial partial lipodystrophy disease (FPLD) is a collection of rare genetic diseases featuring partial loss of adipose tissue. However, metabolic difficulties, such as severe insulin resistance, diabetes, hypertriglyceridemia, and hypertension frequently occur alongside adipose tissue loss, making it susceptible to misdiagnosis and delaying effective treatment. Numerous genes are implicated in the occurrence of FPLD, and genetic testing has been for conditions linked to single gene mutation related to FPLD. Reviewing recent reports, treatment of the disease is limited to preventing and improving complications in patients. CASE SUMMARY In 2017, a 31-year-old woman with diabetes, hypertension and hypertriglyceridemia was hospitalized. We identified a mutation in her peroxisome proliferator-activated receptor gamma (PPARG) gene, Y151C (p.Tyr151Cys), which results in a nucleotide substitution residue 452 in the DNA-binding domain (DBD) of PPARG. The unaffected family member did not carry this mutation. Pioglitazone, a PPARG agonist, improved the patient's responsiveness to hypoglycemic and antihypertensive therapy. After one year of treatment in our hospital, the fasting blood glucose and glycosylated hemoglobin of the patient were close to normal. CONCLUSION We report a rare PPARG mutation, Y151C, which is located in the DBD of PPARG and leads to FPLD, and the preferred agent is PPARG agonists. We then summarized clinical phenotypic characteristics of FPLD3 caused by PPARG gene mutations, and clarified the relationship between different mutations of PPARG gene and the clinical manifestations of this type of FPLD. Additionally, current treatments for FPLD caused by PPARG mutations are reviewed.
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Affiliation(s)
- Chao-Jun Wu
- Basic Medical College, Army Medical University, Chongqing 400038, China
| | - Hao Liu
- Basic Medical College, Army Medical University, Chongqing 400038, China
| | - Li-Juan Tu
- Department of Endocrinology, Rare Disease Center, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China
| | - Jiong-Yu Hu
- Department of Endocrinology, Rare Disease Center, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China
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Soares RMV, da Silva MA, Campos JTADM, Lima JG. Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features. Front Endocrinol (Lausanne) 2024; 15:1394102. [PMID: 39398333 PMCID: PMC11466747 DOI: 10.3389/fendo.2024.1394102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
The PPARG gene encodes a member of a nuclear receptor superfamily known as peroxisome proliferator-activated gamma (PPARγ). PPARγ plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3). This review focuses on recent scientific data related to FPLD3, including the role of PPARγ in adipose tissue metabolism and the phenotypic and clinical consequences of loss-of-function variants in the PPARG gene. The clinical features of 41 PPARG pathogenic variants associated with FPLD3 patients were reviewed, highlighting the genetic and clinical heterogeneity observed among 91 patients. Most of them were female, and the average age at the onset and diagnosis of lipoatrophy was 21 years and 33 years, respectively. Considering the metabolic profile, hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension (59.5%), polycystic ovary syndrome (58.2% of women), and metabolic-dysfunction-associated fatty liver disease (87,5%). We also discuss the current treatment for FPLD3. This review provides new data concerning the genetic and clinical heterogeneity in FPLD3 and highlights the importance of further understanding the genetics of this rare disease.
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Affiliation(s)
- Reivla Marques Vasconcelos Soares
- Department of Clinical Medicine, Hospital Universitário Onofre Lopes (HUOL), Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil
| | - Monique Alvares da Silva
- Molecular Biology and Genomics Laboratory, Federal University of Rio Grande do Norte
(UFRN), Natal, RN, Brazil
| | - Julliane Tamara Araújo de Melo Campos
- Molecular Biology and Genomics Laboratory, Federal University of Rio Grande do Norte
(UFRN), Natal, RN, Brazil
- Department of Morphology (DMOR), Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil
| | - Josivan Gomes Lima
- Department of Clinical Medicine, Hospital Universitário Onofre Lopes (HUOL), Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil
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3
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da Silva MA, Soares RMV, de Oliveira Filho AF, Campos LRS, de Lima JG, de Melo Campos JTA. Case report: two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil. Diabetol Metab Syndr 2024; 16:145. [PMID: 38951919 PMCID: PMC11218129 DOI: 10.1186/s13098-024-01387-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/21/2024] [Indexed: 07/03/2024] Open
Abstract
INTRODUCTION AND AIM Type 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants. MATERIALS AND METHODS Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins. RESULTS We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein. CONCLUSION Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.
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Affiliation(s)
- Monique Alvares da Silva
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte - UFRN, Campus Universitário, Lagoa Nova, Natal, RN, 59072-970, Brazil
| | - Reivla Marques Vasconcelos Soares
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte - UFRN, Natal, RN, Brazil
| | | | - Leonardo René Santos Campos
- Bioinformatics Multidisciplinary Environment, Universidade Federal do Rio Grande do Norte - UFRN, Natal, RN, Brazil
| | - Josivan Gomes de Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte - UFRN, Natal, RN, Brazil
| | - Julliane Tamara Araújo de Melo Campos
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte - UFRN, Campus Universitário, Lagoa Nova, Natal, RN, 59072-970, Brazil.
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Adeva-Andany MM, Domínguez-Montero A, Adeva-Contreras L, Fernández-Fernández C, Carneiro-Freire N, González-Lucán M. Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases. Curr Diabetes Rev 2024; 20:e160823219824. [PMID: 37587805 DOI: 10.2174/1573399820666230816111624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/28/2023] [Accepted: 05/31/2023] [Indexed: 08/18/2023]
Abstract
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Alberto Domínguez-Montero
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | - Carlos Fernández-Fernández
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Natalia Carneiro-Freire
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Manuel González-Lucán
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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Chen X, Ma Z, Chen P, Song X, Li W, Yu X, Xie J. Case Report: A New Peroxisome Proliferator-Activated Receptor Gamma Mutation Causes Familial Partial Lipodystrophy Type 3 in a Chinese Patient. Front Endocrinol (Lausanne) 2022; 13:830708. [PMID: 35422762 PMCID: PMC9001891 DOI: 10.3389/fendo.2022.830708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/23/2022] [Indexed: 11/18/2022] Open
Abstract
PURPOSE Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disease. Patients typically present with loss of adipose tissue and metabolic complications. Here, we reported a Chinese FPLD3 patient with a novel PPARG gene mutation. METHODS A 16-year-old female patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequencing was performed by using the extracted DNA. Moreover, we identified FPLD3 patients from previous studies, and according to the protein region affected by the gene mutation. We divided the patients into the DNA-binding domain (DBD) group or the ligand-binding domain (LBD) group, and compared the clinical features between the two groups. RESULTS We identified a novel gene mutation affecting the LBD of PPARγ c.929T > C (p.F310S). This mutation leads to the substitution of a phenylalanine by a serine. In our case, subcutaneous fat was significantly diminished in her face, hips and limbs. The patient was also presented with insulin resistance, diabetes mellitus, hypertriglyceridemia, fatty liver, liver dysfunction, albuminuria and diabetic peripheral neuropathy. After literature review, a total of 58 FPLD3 patients were identified and we found no difference in clinical features between the DBD group and LBD group (all P > 0.05). CONCLUSIONS A Chinese FPLD3 patient with a novel PPARG gene mutation is described. Our case emphasized the importance of physical examination and genetic testing in young patients with severe metabolic syndromes.
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Affiliation(s)
- Xi Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Internal Medicine, Branch of National Clinical Research Center for Metabolic Disease, Wuhan, China
| | - Zhiqiang Ma
- Division of Cardiology, Departments of Internal Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Chen
- Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Internal Medicine, Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiological Disorders, Wuhan, China
| | - Xiuli Song
- Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Internal Medicine, Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiological Disorders, Wuhan, China
| | - Weihua Li
- Division of Cardiology, Departments of Internal Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuefeng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Internal Medicine, Branch of National Clinical Research Center for Metabolic Disease, Wuhan, China
| | - Junhui Xie
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Internal Medicine, Branch of National Clinical Research Center for Metabolic Disease, Wuhan, China
- *Correspondence: Junhui Xie,
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Lambadiari V, Kountouri A, Maratou E, Liatis S, Dimitriadis GD, Karpe F. Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance. Front Endocrinol (Lausanne) 2021; 12:684182. [PMID: 34168618 PMCID: PMC8217860 DOI: 10.3389/fendo.2021.684182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/18/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (PPARG) gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce. CASE PRESENTATION We present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARGGlu157Gly variant. After six months of metreleptin treatment, HbA1c decreased from 10 to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl. CONCLUSIONS This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.
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Affiliation(s)
- Vaia Lambadiari
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
- *Correspondence: Vaia Lambadiari,
| | - Aikaterini Kountouri
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Eirini Maratou
- Department of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic and Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George D. Dimitriadis
- Medical School, Sector of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, United Kingdom
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7
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Chao X, Guo L, Wang Q, Huang W, Liu M, Luan K, Jiang J, Lin S, Nie Q, Luo W, Zhang X, Luo Q. miR-429-3p/ LPIN1 Axis Promotes Chicken Abdominal Fat Deposition via PPARγ Pathway. Front Cell Dev Biol 2020; 8:595637. [PMID: 33425901 PMCID: PMC7793751 DOI: 10.3389/fcell.2020.595637] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/04/2020] [Indexed: 12/14/2022] Open
Abstract
To explore the regulatory mechanism of abdominal fat deposition in broilers, 100-day-old Sanhuang chickens (n = 12) were divided into high-fat and low-fat groups, according to the abdominal fat ratio size. Total RNA isolated from the 12 abdominal fat tissues was used for miRNA and mRNA sequencing. Results of miRNA and mRNA sequencing revealed that miR-429-3p was highly expressed in high-fat chicken whereas LPIN1 expression was downregulated. Further, we determined that miR-429-3p promoted preadipocyte proliferation and differentiation, whereas LPIN1 exerted an opposite effect. Notably, we found that the miR-429-3p/LPIN1 axis facilitated PPARγ pathway activation, which is closely associated with the progression of adipogenesis. In conclusion, our results provide evidence that a novel miR-429-3p/LPIN1 axis is involved in the regulation of adipogenesis, which may have a guiding role in the improvement of breeding for abdominal fat traits in broiler chickens.
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Affiliation(s)
- Xiaohuan Chao
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Lijin Guo
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qi Wang
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Weiling Huang
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Manqing Liu
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Kang Luan
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jinqi Jiang
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Shudai Lin
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qinghua Nie
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wen Luo
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xiquan Zhang
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qingbin Luo
- Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China.,College of Animal Science, South China Agricultural University, Guangzhou, China
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Bagias C, Xiarchou A, Bargiota A, Tigas S. Familial Partial Lipodystrophy (FPLD): Recent Insights. Diabetes Metab Syndr Obes 2020; 13:1531-1544. [PMID: 32440182 PMCID: PMC7224169 DOI: 10.2147/dmso.s206053] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 03/31/2020] [Indexed: 12/16/2022] Open
Abstract
Lipodystrophies are a heterogeneous group of congenital or acquired disorders, characterized by partial or generalized loss of adipose tissue. Familial partial lipodystrophy (FPLD) presents with genetic and phenotypic variability with insulin resistance, hypertriglyceridemia and hepatic steatosis being the cardinal metabolic features. The severity of the metabolic derangements is in proportion with the degree of lipoatrophy. The underpinning pathogenetic mechanism is the limited capacity of adipose tissue to store lipids leading to lipotoxicity, low-grade inflammation, altered adipokine secretion and ectopic fat tissue accumulation. Advances in molecular genetics have led to the discovery of new genes and improved our knowledge of the regulation of adipose tissue biology. Diagnosis relies predominantly on clinical findings, such as abnormal fat tissue topography and signs of insulin resistance and is confirmed by genetic analysis. In addition to anthropometry and conventional imaging, new techniques such as color-coded imaging of fat depots allow more accurate assessment of the regional fat distribution and differentiation of lipodystrophic syndromes from common metabolic syndrome phenotype. The treatment of patients with lipodystrophy has proven to be challenging. The use of a human leptin analogue, metreleptin, has recently been approved in the management of FPLD with evidence suggesting improved metabolic profile, satiety, reproductive function and self-perception. Preliminary data on the use of glucagon-like peptide 1 receptor agonists (GLP1 Ras) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in cases of FPLD have shown promising results with reduction in total insulin requirements and improvement in glycemic control. Finally, investigational trials for new therapeutic agents in the management of FPLD are underway.
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Affiliation(s)
- Christos Bagias
- Department of Endocrinology, University of Ioannina, Ioannina, Greece
| | - Angeliki Xiarchou
- Department of Endocrinology, University of Ioannina, Ioannina, Greece
| | | | - Stelios Tigas
- Department of Endocrinology, University of Ioannina, Ioannina, Greece
- Correspondence: Stelios Tigas Department of Endocrinology, University of Ioannina, Ioannina45110, GreeceTel +30 2651007800 Email
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9
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Abstract
Lipodystrophies are the result of a range of inherited and acquired causes, but all are characterized by perturbations in white adipose tissue function and, in many instances, its mass or distribution. Though patients are often nonobese, they typically manifest a severe form of the metabolic syndrome, highlighting the importance of white fat in the "safe" storage of surplus energy. Understanding the molecular pathophysiology of congenital lipodystrophies has yielded useful insights into the biology of adipocytes and informed therapeutic strategies. More recently, genome-wide association studies focused on insulin resistance have linked common variants to genes implicated in adipose biology and suggested that subtle forms of lipodystrophy contribute to cardiometabolic disease risk at a population level. These observations underpin the use of aligned treatment strategies in insulin-resistant obese and lipodystrophic patients, the major goal being to alleviate the energetic burden on adipose tissue.
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10
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Broekema M, Savage D, Monajemi H, Kalkhoven E. Gene-gene and gene-environment interactions in lipodystrophy: Lessons learned from natural PPARγ mutants. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:715-732. [PMID: 30742913 DOI: 10.1016/j.bbalip.2019.02.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/13/2019] [Accepted: 02/02/2019] [Indexed: 12/13/2022]
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11
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Guo S, Lu H. Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α. J Cell Biochem 2019; 120:519-532. [PMID: 30191603 PMCID: PMC7745837 DOI: 10.1002/jcb.27407] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/10/2018] [Indexed: 12/13/2022]
Abstract
Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of development and function of digestive tissues. The HNF4A gene uses two separate promoters P1 and P2, with P1 products predominant in adult liver, whereas P2 products prevalent in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for the regulation of HNF4A and the dynamic switch of P1-HNF4α and P2-HNF4α during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4α but invalidated the reported synergism between HNF4α and HNF1α. HNF4A-AS1, a long noncoding RNA, is localized between the P2 and P1 promoters of HNF4A. We identified critical roles of P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog Hnf4a-os. Paired box 6 (PAX6), a master regulator of pancreas development overexpressed in colon cancer, cooperated with HNF1α to induce P2-HNF4α but antagonized HNF4α in HNF4A-AS1 expression. Thus, PAX6 may be important in determining ontogenic and carcinogenic changes of P2-HNF4α and HNF4A-AS1 in the pancreas and intestine. We also interrogated transactivation activities on multiple gene targets by multiple known and novel HNF4α mutants identified in patients with maturity onset diabetes of the young 1 (MODY1) and liver cancer. Particularly, HNF4α-D78A and HNF4α-G79S, two mutants found in liver cancer with mutations in DNA-binding domain, displayed highly gene-specific transactivation activities. Interestingly, HNF4α-Q277X, a MODY1 truncation mutant, antagonized the transactivation activities of HNF1α and farnesoid X receptor, key regulators of insulin secretion. Taken together, our study provides novel mechanistic insights regarding the transcriptional regulation and transactivation activity of HNF4α in digestive tissues.
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Affiliation(s)
- Shangdong Guo
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S
| | - Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S
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Quantitative PPARγ expression affects the balance between tolerance and immunity. Sci Rep 2016; 6:26646. [PMID: 27221351 PMCID: PMC4879582 DOI: 10.1038/srep26646] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 05/06/2016] [Indexed: 01/21/2023] Open
Abstract
PPARγ modulates energy metabolism and inflammation. However, its specific functions in the balance of immunity in vivo have been explored incompletely. In this study, by the age of 14 mo, PpargC/− mice with PPARγ expression at 25% of the normal level exhibited high autoantibody levels and developed mesangial proliferative glomerulonephritis, which resembled systemic lupus erythematosus (SLE)-like autoimmune disease. These symptoms were preceded by splenomegaly at an early age, which was associated with increases in splenocyte accumulation and B-cell activation but not with relocation of hematopoiesis to the spleen. The mechanism of splenic lymphocyte accumulation involved reduced sphingosine-1-phosphate receptor 1 (S1P1) expression and diminished migration toward S1P in the PpargC/− splenocytes, which impeded lymphocyte egression. Mechanistically, increased Th17 polarization and IL-17 signaling in the PpargC/− CD4+ T cells contributed to B-cell hyperactivation in the spleen. Finally, the activation of the remaining PPARγ in PpargC/− mice by pioglitazone increased S1P1 levels, reduced the Th17 population in the spleen, and ameliorated splenomegaly. Taken together, our data demonstrated that reduction of Pparg expression in T-helper cells is critical for spontaneous SLE-like autoimmune disease development; we also revealed a novel function of PPARγ in lymphocyte trafficking and cross talk between Th17 and B cells.
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Lu W, Wang W, Wang S, Feng Y, Liu K. Rosiglitazone Promotes Bone Marrow Adipogenesis to Impair Myelopoiesis under Stress. PLoS One 2016; 11:e0149543. [PMID: 26895498 PMCID: PMC4760757 DOI: 10.1371/journal.pone.0149543] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 02/02/2016] [Indexed: 01/04/2023] Open
Abstract
Objective The therapeutic use of thiazolidinediones (TZDs) causes unwanted hematological side effects, although the underlying mechanisms of these effects are poorly understood. This study tests the hypothesis that rosiglitazone impairs the maintenance and differentiation of hematopoietic stem/progenitor cells, which ultimately leads to hematological abnormalities. Methods Mice were fed a rosiglitazone-supplemented diet or a normal diet for 6 weeks. To induce hematopoietic stress, all mice were injected once with 250 mg/kg 5-fluorouracil (5-Fu) intraperitoneally. Next, hematopoietic recovery, hematopoietic stem/progenitor cells (HSPCs) subsets, and myeloid differentiation after 5-Fu treatment were evaluated. The adipogenesis induced by rosiglitazone was assessed by histopathology and oil red O staining. The effect of adipocytes on HSPCs was studied with an in vitro co-culture system. Results Rosiglitazone significantly enhanced bone marrow adipogenesis and delayed hematopoietic recovery after 5-Fu treatment. Moreover, rosiglitazone inhibited proliferation of a granulocyte/monocyte progenitor (GMP) cell population and granulocyte/macrophage colony-stimulating factor (GM-CSF) colonies, although the proliferation and mobilization of Lin-c-kit+Sca-1+ cells (LSK) was maintained following hematopoietic stress. These effects could be partially reversed by the selective PPARγ antagonist BADGE. Finally, we demonstrated in a co-culture system that differentiated adipocytes actively suppressed the myeloid differentiation of HSPCs. Conclusion Taken together, our results demonstrate that rosiglitazone inhibits myeloid differentiation of HSPCs after stress partially by inducing bone marrow adipogenesis. Targeting the bone marrow microenvironment might be one mechanism by which rosiglitazone impairs stress-induced hematopoiesis.
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Affiliation(s)
- Wenyi Lu
- Department of Hematology, Peking University People’s Hospital, Beijing, China
- Institute of Hematology, Peking University, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Weimin Wang
- Department of Hematology, Peking University People’s Hospital, Beijing, China
- Institute of Hematology, Peking University, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Shujuan Wang
- Department of Hematology, Peking University People’s Hospital, Beijing, China
- Institute of Hematology, Peking University, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yonghuai Feng
- Department of Hematology, Peking University People’s Hospital, Beijing, China
- Institute of Hematology, Peking University, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Kaiyan Liu
- Department of Hematology, Peking University People’s Hospital, Beijing, China
- Institute of Hematology, Peking University, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, China
- * E-mail:
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Miehle K, Porrmann J, Mitter D, Stumvoll M, Glaser C, Fasshauer M, Hoffmann K. Novel peroxisome proliferator-activated receptor gamma mutation in a family with familial partial lipodystrophy type 3. Clin Endocrinol (Oxf) 2016; 84:141-8. [PMID: 26119484 DOI: 10.1111/cen.12837] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/20/2015] [Accepted: 06/17/2015] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder with loss of subcutaneous adipose tissue at the extremities and metabolic complications such as insulin resistance, hypertriglyceridaemia and hypertension. The aim of this study was to characterize the molecular basis of a family of 5 affected members with FPLD3. METHODS A 61-year-old female index patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequence analysis of the LMNA and PPARG gene was performed. Structure analysis of the identified mutation was carried out using published X-ray crystal structures. RESULTS A novel heterozygous PPARG mutation c.1040A>C was identified in all 5 patients of the family but not in unaffected controls. The resulting amino acid substitution p.Lys347Thr is located at the ligand-binding domain (LBD) of the protein and is predicted to disrupt critical molecular interactions to the helix 12 of the LBD. CONCLUSIONS A novel PPARG mutation leading to FPLD3 is described. The results emphasize the importance of the clinical diagnosis and of further molecular genetic analyses in patients with clinical signs of FPLD but unremarkable LMNA findings.
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Affiliation(s)
- Konstanze Miehle
- Department of Internal Medicine (Endocrinology and Nephrology), University of Leipzig, Leipzig, Germany
| | - Joseph Porrmann
- Department of Human Genetics, University of Halle, Halle, Germany
| | - Diana Mitter
- Department of Human Genetics, University of Leipzig, Leipzig, Germany
| | - Michael Stumvoll
- Department of Internal Medicine (Endocrinology and Nephrology), University of Leipzig, Leipzig, Germany
| | | | - Mathias Fasshauer
- Department of Internal Medicine (Endocrinology and Nephrology), University of Leipzig, Leipzig, Germany
- Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany
| | - Katrin Hoffmann
- Department of Human Genetics, University of Halle, Halle, Germany
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Effects of Citral on Lipopolysaccharide-Induced Inflammation in Human Umbilical Vein Endothelial Cells. Inflammation 2015; 39:663-71. [DOI: 10.1007/s10753-015-0292-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Shao G, Tian Y, Wang H, Liu F, Xie G. Protective effects of melatonin on lipopolysaccharide-induced mastitis in mice. Int Immunopharmacol 2015; 29:263-268. [PMID: 26590117 DOI: 10.1016/j.intimp.2015.11.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 10/18/2015] [Accepted: 11/06/2015] [Indexed: 12/17/2022]
Abstract
Melatonin, a secretory product of the pineal gland, has been reported to have antioxidant and anti-inflammatory effects. However, the protective effects of melatonin on lipopolysaccharide (LPS)-induced mastitis have not been reported. The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of melatonin on LPS-induced mastitis both in vivo and in vitro. In vivo, our results showed that melatonin attenuated LPS-induced mammary histopathologic changes and myeloperoxidase (MPO) activity. Melatonin also inhibited LPS-induced inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) production in mammary tissues. In vitro, melatonin was found to inhibit LPS-induced TNF-α and IL-6 production in mouse mammary epithelial cells. Melatonin also suppressed LPS-induced Toll-like receptor 4 (TLR4) expression and nuclear factor-kappaB (NF-κB) activation in a dose-dependent manner. In addition, melatonin was found to up-regulate the expression of PPAR-γ. Inhibition of PPAR-γ by GW9662 reduced the anti-inflammatory effects of melatonin. In conclusion, we found that melatonin, for the first time, had protective effects on LPS-induced mastitis in mice. The anti-inflammatory mechanism of melatonin was through activating PPAR-γ which subsequently inhibited LPS-induced inflammatory responses.
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Affiliation(s)
- Guoxi Shao
- The Second Hospital of Jilin University, China
| | - Yinggang Tian
- State Key Laboratory of Food Science and Technology, Nanchang University, 235 East Nanjing Road, Nanchang 330047, China
| | - Haiyu Wang
- College of Veterinary Medicine, Jilin University, China
| | - Fangning Liu
- College of Veterinary Medicine, Jilin University, China
| | - Guanghong Xie
- College of Veterinary Medicine, Jilin University, China.
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Dyment DA, Gibson WT, Huang L, Bassyouni H, Hegele RA, Innes AM. Biallelic mutations at PPARG cause a congenital, generalized lipodystrophy similar to the Berardinelli-Seip syndrome. Eur J Med Genet 2014; 57:524-6. [PMID: 24980513 DOI: 10.1016/j.ejmg.2014.06.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 06/20/2014] [Indexed: 10/25/2022]
Abstract
We present an individual with a generalized and infantile onset lipodystrophy who later developed hypertriglyceridemia, pancreatitis, refractory diabetes, irregular menses and renal failure. She showed the hallmark features of a congenital, generalized lipodystrophy (CGL). Sequencing PPARG identified two pathogenic mutations; c.413_416delAATG; p.Glu138ValfsX168 and c.490C>T; p.R164W. The phenotype and presence of two mutations suggests that biallelic mutations at PPARG cause a CGL similar to that observed with biallelic AGPAT2 or BSCL2 mutations.
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Affiliation(s)
- D A Dyment
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
| | - W T Gibson
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
| | - L Huang
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
| | - H Bassyouni
- Department of Endocrinology and Metabolism, University of Calgary, Calgary, Canada
| | - R A Hegele
- Robarts Research Institute, University of Western Ontario, London, Canada
| | - A M Innes
- Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Canada
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Sigmund CD. A clinical link between peroxisome proliferator-activated receptor γ and the renin-angiotensin system. Arterioscler Thromb Vasc Biol 2013; 33:676-8. [PMID: 23486770 DOI: 10.1161/atvbaha.112.301125] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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