Disentangling the detrimental effects of local from systemic adipose tissue dysfunction on articular cartilage in the knee.

Objective: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed.

Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.

Lipodystrophy syndromes are rare diseases primarily affecting the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, often leading to reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmunity in the vast majority of cases. While many subtypes are now recognized and classified, the disease remains remarkably underdiagnosed.

From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy.

Aims: Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise.

Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy.

Congenital generalized lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the gene, which encodes the protein seipin. Patients with congenital generalized lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes, and cardiovascular disease.

Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy.

Congenital Generalized Lipodystrophy type 2 (CGL2) is the most severe form of lipodystrophy and is caused by mutations in the gene. Affected patients exhibit a near complete lack of adipose tissue and suffer severe metabolic disease. A recent study identified infection as a major cause of death in CGL2 patients, leading us to examine whether loss could directly affect the innate immune response.

High-fat diet exacerbates cognitive and metabolic abnormalities in neuronal BACE1 knock-in mice - partial prevention by Fenretinide.

The β-site APP-cleaving enzyme 1 (BACE1) is a rate-limiting step in β-amyloid (Aβ) production in Alzheimer's disease (AD) brains, but recent evidence suggests that BACE1 is also involved in metabolic regulation. Here, we aimed to assess the effects of highfat diet (HFD) on metabolic and cognitive phenotypes in the diabetic BACE1 knock-in mice (PLB4) and WT controls; we additionally examined whether these phenotypes can be normalized with a synthetic retinoid (Fenretinide, Fen) targeting weight loss. Five-month old male WT and PLB4 mice were fed either (1) control chow diet, (2) 45%-saturated fat diet (HFD), (3) HFD with 0.

Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation.

Seipin deficiency causes severe congenital generalized lipodystrophy (CGL) and metabolic disease. However, how seipin regulates adipocyte development and function remains incompletely understood. We previously showed that seipin acts as a scaffold protein for AGPAT2, whose disruption also causes CGL.

Ablation of /seipin in hepatocytes does not cause metabolic dysfunction in congenital generalised lipodystrophy.

Mutations affecting the gene cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals develop severe metabolic complications including diabetes and hepatic steatosis. -deficient mice almost entirely reproduce the CGL phenotype.

Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.

Objective: Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans.

Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice.

Fibroblast growth factor 21 (FGF21) has emerged as an important beneficial regulator of glucose and lipid homeostasis but its levels are also abnormally increased in insulin-resistant states in rodents and humans. The synthetic retinoid Fenretinide inhibits obesity and improves glucose homeostasis in mice and has pleotropic effects on cellular pathways. To identify Fenretinide target genes, we performed unbiased RNA-seq analysis in liver from mice fed high-fat diet ± Fenretinide.

Fenretinide mediated retinoic acid receptor signalling and inhibition of ceramide biosynthesis regulates adipogenesis, lipid accumulation, mitochondrial function and nutrient stress signalling in adipocytes and adipose tissue.

Fenretinide (FEN) is a synthetic retinoid that inhibits obesity and insulin resistance in high-fat diet (HFD)-fed mice and completely prevents 3T3-L1 pre-adipocyte differentiation. The aim of this study was to determine the mechanism(s) of FEN action in 3T3-L1 adipocytes and in mice. We used the 3T3-L1 model of adipogenesis, fully differentiated 3T3-L1 adipocytes and adipose tissue from HFD-induced obese mice to investigate the mechanisms of FEN action.

Fenretinide prevents obesity in aged female mice in association with increased retinoid and estrogen signaling.

Objective: The synthetic retinoid fenretinide (FEN) inhibits adiposity in male mice fed a high-fat diet (HFD) in association with alterations in retinoic acid (RA) signaling. Young female mice are protected from obesity via estrogen signaling. We, therefore, investigated whether FEN also influences adiposity in aged female mice differing in parity and whether such effects are mediated by retinoid and estrogen signaling.

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes.

Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways.

Fenretinide treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene expression in adipose, liver, and hypothalamus.

The synthetic retinoid, Fenretinide (FEN), inhibits obesity and insulin resistance in mice and is in early clinical trials for treatment of insulin resistance in obese humans. We aimed to determine whether alterations in retinoic acid (RA)-responsive genes contribute to the beneficial effects of FEN. We examined the effect of FEN on 3T3-L1 adipocyte differentiation and alterations in gene expression in C57Bl/6 and retinaldehyde dehydrogenase (RALDH) 1 knockout (KO) mice fed a high-fat (HF) diet.

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis.

Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s) of adipose-PTP1B-deficiency on body mass and insulin resistance.

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction.

Mutations in mitochondrial oxidative phosphorylation complex I are associated with multiple pathologies, and complex I has been proposed as a crucial regulator of animal longevity. In yeast, the single-subunit NADH dehydrogenase Ndi1 serves as a non-proton-translocating alternative enzyme that replaces complex I, bringing about the reoxidation of intramitochondrial NADH. We have created transgenic strains of Drosophila that express yeast NDI1 ubiquitously.

Production of reactive oxygen species by the mitochondrial electron transport chain in Drosophila melanogaster.

Mitochondrial free radicals and in particular mitochondrial Reactive Oxygen Species (mtROS) are considered to be totally or partially responsible for several different diseases including Parkinson, diabetes or cancer. Even more importantly, mtROS have also been proposed as the main driving force behind the aging process. Thus, in the last decade, there has been a growing interest in the role of free radicals as signalling molecules.