Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.

Lipodystrophy is a rare disease characterized by loss of adipose tissue. Natural history studies have demonstrated significant burden of disease; however, there is limited data on the impact of lipodystrophy on quality of life (QoL) and psychoemotional well-being. The QuaLip study is a prospective observational real-world study that aims to determine the impact of lipodystrophy on QoL and psychoemotional well-being and explore subjective burden of the disease. Sixty-seven adult patients and eight pediatric patients with lipodystrophy were included. Patients were followed up for 24 months and assessments were repeated every three months. Patients were examined by licensed psychiatrists at baseline, and at year 1 and year 2 visits.

Eighteen (27.69%) of 65 adult patients (two subjects refused psychiatric assessment) were diagnosed with a psychiatric disorder (e.g., depressive episodes, mixed anxiety and depressive disorder, anxiety disorder, adjustment disorder, recurrent depression, panic disorder, generalized anxiety disorder, unspecified mood disorder, nonorganic sleep disorder, post-traumatic stress disorder, depressive episode comorbidity, social phobia and obsessive-compulsive disorder comorbidity). Lipodystrophy disease and QoL questionnaires revealed a significant disease burden over the study period. More than one-third of patients reported depression symptoms on the Beck Depression Inventory and more than one-fourth of the patients reported significant hunger throughout the study period. Physical appearance, fatigue, and pain contributed to the disease burden. QoL scores were lower in patients with psychiatric disease and in those with poor metabolic control. Attention deficit hyperactivity disorder, depressive disorder, sub-threshold depressive symptoms, obsessive-compulsive disorder, appetite problems, and issues with physical appearance were identified in selected pediatric subjects.

Lipodystrophy has a significant impact on QoL and psychoemotional well-being. Psychiatric disorders seem to be underdiagnosed among patients with lipodystrophy.

This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.

To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting.

Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment.

Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m² and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group.

In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.

Insulin resistance (IR) is insulin failure in normal plasma levels to adequately stimulate glucose uptake by the peripheral tissues. IR is becoming more common in children and adolescents than before. There is a strong association between obesity in children and adolescents, IR, and the metabolic syndrome components. IR shows marked variation among different races, crucial to understanding the possible cardiovascular risk, specifically in high-risk races or ethnic groups. Genetic causes of IR include insulin receptor mutations, mutations that stimulate autoantibody production against insulin receptors, or mutations that induce the formation of abnormal glucose transporter 4 molecules or plasma cell membrane glycoprotein-1 molecules; all induce abnormal energy pathways and end with the development of IR. The parallel increase of IR syndrome with the dramatic increase in the rate of obesity among children in the last few decades indicates the importance of environmental factors in increasing the rate of IR. Most patients with IR do not develop diabetes mellitus (DM) type-II. However, IR is a crucial risk factor to develop DM type-II in children. Diagnostic standards for IR in children are not yet established due to various causes. Direct measures of insulin sensitivity include the hyperinsulinemia euglycemic glucose clamp and the insulin-suppression test. Minimal model analysis of frequently sampled intravenous glucose tolerance test and oral glucose tolerance test provide an indirect estimate of metabolic insulin sensitivity/resistance. The main aim of the treatment of IR in children is to prevent the progression of compensated IR to decompensated IR, enhance insulin sensitivity, and treat possible complications. There are three main lines for treatment: Lifestyle and behavior modification, pharmacotherapy, and surgery. This review will discuss the magnitude, implications, diagnosis, and treatment of IR in children.