leptin and Aging--Premature

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Topics: Adipocytes; Adipose Tissue; Aging, Premature; Humans; Inflammation; Insulin Resistance; Leptin; Lipodystrophy; Lipomatosis; Syndrome

Topics: Acro-Osteolysis; Adipose Tissue; Aging, Premature; Body Composition; Cardiovascular System; Combined Modality Therapy; Diabetes Mellitus; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Erythema Nodosum; Fingers; Genes, Dominant; Humans; Hypoglycemic Agents; Insulin; Leptin; Lipodystrophy; Lipodystrophy, Familial Partial; Mandible; Metformin; Musculoskeletal Diseases; Phenotype; Recombinant Proteins; Surgery, Plastic; Werner Syndrome

"Accelerated aging," assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age.. DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA; preserved across cell types) and extrinsic (EEAA; dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development.. In 995 participants (49.6% female; age, 17.3 ± 0.6 years), EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% (95% CI, 1.2% to 3.6%) and 2.4% (0.8% to 3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3% to 33%) in high-sensitivity C-reactive protein, 10% (4% to 17%) in interferon-γ-inducible protein of 10 kDa, and 4% (2% to 6%) in soluble TNF receptor 2, adjusted for BMI and HOMA-IR. EEAA (per 5 years) results in a 4% increase in hard endpoints of CVD by 47 years of age and a 3% increase, after adjustment for conventional risk factors.. Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle age CVD. Irrespective of whether this is cause or effect, assessing epigenetic age might refine disease prediction.

Topics: Absorptiometry, Photon; Adiponectin; Adolescent; Aging; Aging, Premature; Algorithms; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Chemokine CXCL10; Cholesterol, HDL; Cholesterol, LDL; DNA Methylation; Epigenesis, Genetic; Female; Humans; Inflammation; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-18; Leptin; Male; Middle Aged; Receptors, Tumor Necrosis Factor, Type II; Risk Assessment; Risk Factors; Western Australia; Young Adult