Molecular and Cellular Bases of Lipodystrophy Syndromes

Abstract

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.

Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

“…We further demonstrated the utility of our tissue atlas for monogenic and polygenic disease biology. Many monogenic disease gene modules that are defined by comorbidity [e.g., diabetes and lipodystrophy ( 174 )] or similarity of clinical phenotypes (e.g., muscle diseases) were enriched in expected cell types (fig. S35F).…”

Role of insulin resistance on fertility – Focus on polycystic ovary syndrome

“…Adipokines produced by adipose tissue also display important regulatory roles on the reproductive axis [21]. Defects in adipocyte differentiation and/or functions are the main determinants of lipodystrophy syndromes, associated with insulin resistance and PCOS features [10,11,[14][15][16][17][19][20][21][22][23][24]. Leptin deficiency due to lipoatrophy contributes to insulin resistance, as shown by the metabolic benefit of substitutive therapy with the leptin analog metreleptin in generalized lipoatrophy [22].…”

Qualitative interviews in patients with lipodystrophy to assess the patient experience: evaluation of hunger and other symptoms

“…Both GLD and PLD can be due to gene mutations (congenital generalized lipodystrophy [CGL] and familial PLD [FPL], respectively) [ 4 , 5 ]. CGL is due to mutations in any one of four genes, designated CGL1-4, whereas FPL can be due to mutations in any one of six or more genes, designated FPLD2-7.…”

“…FPLD1, or Kobberling’s syndrome, is not a monogenic disorder but has a strong familial component. In addition, both GLD and PLD can be acquired, resulting from other conditions such as autoimmune diseases characterized by immune destruction of leptin-producing adipocytes [ 4 , 5 , 8 ].…”