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Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduc...
Citations
... Exploring the correlation between leptin levels and diabetes provides valuable insights into potential therapeutic strategies for managing and preventing this prevalent agerelated disease. Administration of leptin as a therapeutic intervention has been documented to ameliorate insulin resistance in muscles and the liver among individuals with lipodystrophy [22][23][24]. Additionally, it has been shown to inhibit liver gluconeogenesis, suppress lipolysis, and mitigate fasting hyperglycemia in animal models with diabetes [25]. ...
... Exploring the correlation between leptin levels and diabetes provides valuable insights into potential therapeutic strategies for managing and preventing this prevalent agerelated disease. Administration of leptin as a therapeutic intervention has been documented to ameliorate insulin resistance in muscles and the liver among individuals with lipodystrophy [22][23][24]. Additionally, it has been shown to inhibit liver gluconeogenesis, suppress lipolysis, and mitigate fasting hyperglycemia in animal models with dia-REVIEW http://www.antpublisher.com/index.php/APT/index ...
Aging, a multifaceted process influenced by genetics, environment, and lifestyle, involves cellular, metabolic, and immune changes. Leptin, a key regulator of appetite and metabolism, contributes to cellular integrity, impacts telomere maintenance, and interacts with insulin and other hormones, influencing metabolic, immune, and neuroendocrine functions. Its role in age-related diseases, such as diabetes, cardiovascular issues, and neurodegenerative conditions, underscores its diverse impact. Studies suggest potential links between altered leptin levels and increased lifespan. Calorie restriction, known to mitigate aging, involves leptin-triggered activation of central SIRT1. The gut microbiome, mediating environmental cues, undergoes age-related shifts, reciprocally affected by leptin. Probiotics may reduce leptin levels, exhibiting anti-obesogenic effects. Bidi-rectional communication between leptin and the gut microbiome emphasizes their intertwined relationship. Leptin supplementation and lifestyle modifications impacting leptin signaling emerge as potential strategies for healthy aging, offering avenues for future research and intervention.
... Leptin was the first adipokine to be described and has a central role in energy, lipid, and carbohydrate metabolism [48][49][50][51]. Nevertheless, the only approved therapeutical application for leptin is the control of metabolic complications in patients with genetic leptin deficiency or in patients with severe adipose tissue restriction (lipodystrophy) [52][53][54][55]. In these patients, leptin supplementation ameliorates insulin resistance, hyperglycemia, hypertriglyceridemia, hepatic steatosis, and female infertility [53,[56][57][58]. ...
Background
Adipose tissue-derived stromal vascular fraction (SVF) harbors multipotent cells with potential therapeutic relevance. We developed a method to form adipose spheroids (AS) from the SVF with complex organoid structure and enhanced leptin secretion upon insulin stimulation.
Methods
SVF was generated from the interscapular brown adipose tissue of newborn mice. Immunophenotype and stemness of cultured SVF were determined by flow cytometry and in vitro differentiation, respectively. Spheroids were generated in hanging drops and non-adherent plates and compared by morphometric methods. The adipogenic potential was compared between preadipocyte monolayers and spheroids. Extracellular leptin was quantified by immunoassay. Lipolysis was stimulated with isoprenaline and quantified by colorimetric methods. AS viability and ultrastructure were determined by confocal and transmission electron microscopy analyses.
Results
Cultured SVF contained Sca1 + CD29 + CD44 + CD11b- CD45- CD90- cells with adipogenic and chondrogenic but no osteogenic potential. Culture on non-adherent plates yielded the highest quantity and biggest size of spheroids. Differentiation of AS for 15 days in a culture medium supplemented with insulin and rosiglitazone resulted in greater Pparg, Plin1, and Lep expression compared to differentiated adipocytes monolayers. AS were viable and maintained leptin secretion even in the absence of adipogenic stimulation. Glycerol release after isoprenaline stimulation was higher in AS compared to adipocytes in monolayers. AS were composed of outer layers of unilocular mature adipocytes and an inner structure composed of preadipocytes, immature adipocytes and an abundant loose extracellular matrix.
Conclusion
Newborn mice adipose SVF can be efficiently differentiated into leptin-secreting AS. Prolonged stimulation with insulin and rosiglitazone allows the formation of structurally complex adipose organoids able to respond to adrenergic lipolytic stimulation.
... The severe phenotype clearly demonstrates the beneficial metabolic effects of having normal AT. Significant but partial correction of the phenotype occurs with leptin treatment [10]. This suggests that the adverse effects are a combination of loss of normal adipokines, especially leptin, plus an inability to "correctly" store lipids in AT, leading to ectopic lipid deposition. ...
Objective:
The goal of this study was to review the metabolic effects of fat transplantation.
Methods:
Fat (adipose tissue [AT]) transplantation has been performed extensively for many years in the cosmetic reconstruction industry. However, not all fats are equal. White, brown, and beige AT differ in energy storage and use. Brown and beige AT consume glucose and lipids for thermogenesis and, theoretically, may provide greater metabolic benefit in transplantation. Here, the authors review the metabolic effects of AT transplantation.
Results:
Removal of subcutaneous human AT does not have beneficial metabolic effects. Most studies find no benefit from visceral AT transplantation and some studies report harmful effects. In contrast, transplantation of inguinal or subcutaneous AT in mice has positive effects. Brown AT transplant studies have variable results depending on the model but most show benefit.
Conclusions:
Many technical improvements have optimized fat grafting and transplantation in cosmetic surgery. Transplantation of subcutaneous AT has the potential for significant metabolic benefits, although there are few studies in humans or using human AT. Brown AT transplantation is beneficial but not readily feasible in humans thus ex vivo "beiging" may be a useful strategy. AT transplantation may provide clinical benefits in metabolic disorders, especially in the setting of lipodystrophy.
... Leptin has been administered to control hyperglycemia in human beings and animals. [3][4][5]9,[26][27][28] In addition, leptin restores glucose homeostasis mainly through its action on the central neural system. 3,4,[28][29][30] Although OBRb was found to be expressed in the liver, [6][7][8] it is contradictory in the literature whether hepatic leptin signaling can suppress gluconeogenesis. ...
Background & Aims
Obesity related hyperglycemia, with hepatic insulin resistance, has become epidemic disease. Central neural leptin signaling was reported to improve hyperglycemia. The aim of this study was to investigate the effect of hepatic leptin signaling on controlling hyperglycemia.
Methods
Firstly, effect of leptin signaling on gluconeogenesis was investigated in primary mouse hepatocytes and hepatoma cells. Secondly, glucose tolerance, insulin tolerance, blood glucose levels and hepatic gluconeogenic gene expression were analyzed in obese mice overexpressing hepatic OBRb. Thirdly, expression of mitogen-activated protein kinase phosphatase (MKP)-3, phosphorylation level of signal transducer and activator of transcription (STAT) 3 and extracellular regulated protein kinase (ERK) were analyzed in hepatocytes and mouse liver. Fourthly, the role of MKP-3 in hepatic leptin signaling regulating gluconeogenesis was analyzed. Lastly, the role of ERK and STAT3 in the regulation of MKP-3 protein by leptin signaling was analyzed.
Results
Activation of hepatic leptin signaling suppressed gluconeogenesis in both hepatocytes and obese mouse liver, and improved hyperglycemia, insulin tolerance and glucose tolerance in obese mice. Protein level of MKP-3, which can promote gluconeogenesis, was decreased by leptin signaling in both hepatocytes and mouse liver. Mkp-3 deficiency abolished the effect of hepatic leptin signaling on suppressing gluconeogenesis in hepatocytes. STAT3 decreased MKP-3 protein level, while inactivation of STAT3 abolished the effect of leptin signaling on reducing MKP-3 protein level in hepatocytes. Moreover, STAT3 could combine with MKP-3 and phospho-ERK1/2, which induced the degradation of MKP-3, and leptin signaling enhanced the combination.
Conclusions
Hepatic leptin signaling could suppress gluconeogenesis at least partially by decreasing MKP-3 protein level via STAT3 enhanced MKP-3 and ERK1/2 combination.
... In patients who develop diabetes, insulin may be used along with metformin treatment (2, 7). The efficacy of recombinant human leptin (metreleptin) in CGL has been shown in many studies (9)(10)(11)(12). Metreleptin reduces appetite through leptin receptors in the hypothalamus (13) and improves peripheral and hepatic insulin sensitivity (14). ...
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by an almost complete absence of body fat. In CGL, patients may have hyperphagia due to leptin deficiency. Recombinant human leptin (metreleptin) has been suggested as an effective treatment option. We, herein, present the successful use of metreleptin in a case with CGL and its 1-year follow-up. An eight-month-old boy presented with complaints of hair growth and muscular appearance: He had, hypertrichosis, decreased subcutaneous adipose tissue in the whole body and hepatomegaly. In the laboratory investigations hypertriglyceridemia, hyperinsulinemia, elevated liver transaminases and low leptin levels were detected. In molecular genetic analysis homozygous c.465_468delGACT (p.T156Rfs*8) mutation was detected in the BSCL2 gene. A diagnosis of CGL type 2 was considered. Despite the dietary intervention, exercises, omega-3 and metformin treatment, the hypertriglyceridemia, hyperinsulinemia, and elevated liver transaminase levels worsened. After one year of metreleptin treatment, hyperphagia disappeared, insulin, HbA1c, triglyceride and liver transaminase levels improved dramatically. Hepatosteatosis reduced, The size of the liver and the spleen remarkably decreased. Metreleptin is an effective treatment option that prevents the development of metabolic complications of CGL in children. The initiation of metreleptin treatment in the early period would decrease mortality and morbidity, and increase the quality of life in children with CGL.
... drugsatfda_docs/label/2014/125390s004lbl.pdf). These preliminary results were afterward endorsed by several studies (49)(50)(51)(52). On May 31, 2018 the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) granted the marketing authorization of metreleptin for patients with GL > 2 years of age and for patients with PL > 12 years of age for whom standard treatments have failed to achieve adequate metabolic control (European Medicines Agency website: https://www.ema.europa.eu/en/medicines/human/ ...
... Acute pancreatitis, can occur also when tapering or acutely interrupting metreleptin therapy (57,70). Autoimmune hepatitis and membranoproliferative glomerulonephritis are also reported, considering metreleptin impact on autoimmunity (49). Occasionally, the same disorders are seen before initiating metreleptin treatment, especially in patients with baseline fatty liver or renal disease secondary to lipodystrophy itself (77). ...
Lipodystrophy includes a heterogeneous group of rare diseases characterized by different amounts of adipose tissue loss and several metabolic complications, including hypertriglyceridemia, steatohepatitis and particularly insulin resistance, that may lead to severe morbidity and, sometimes, mortality. Therefore, therapy for lipodystrophy primarily consists of a conventional approach that involves standard treatments of metabolic abnormalities. Given the evidence of leptin deficiency in lipodystrophy syndromes, leptin replacement therapy has been considered as a treatment option. Long-term studies on the use of therapy with a methionylated analog of human leptin, metreleptin, first on animals and subsequently on human patients, demonstrated enormous improvements of patients’ clinical features and metabolic conditions. Recently, metreleptin was approved by Food and Drug Administration (FDA) for the treatment of generalized lipodystrophy and by European Medicines Agency (EMA) for the treatment of both generalized and partial lipodystrophy. However, further research is being conducted for new and different therapeutic agents, especially helpful for the treatment of patients with partial lipodystrophy, as some of them do not have access to metreleptin therapy or show poor response.
... Most studies address leptin as a potential pharmacological therapy in the control of weight gain and obesity [32,33]. However, the complexity of leptin actions and its differential interactions with other metabolic factors, both in the body and in the brain, requires a deeper understanding of the physiology of leptin in terms of weight gain/loss control [34][35][36][37]. ...
Background:
Obesity and being overweight have been described as potential causes of neurological disorders. Leptin, a peptide expressed in fat tissue, importantly participates in energy homeostasis and storage and has recently been identified for its signaling receptors in neuronal circuits of the brain.
Aim:
To elucidate whether the endogenous modulation of leptin can be a protection against neuropsychiatric disorders.
Method:
A systematic review was performed in accordance with the PRISMA-P method, and reports of studies containing data of leptin concentrations in healthy individuals with or without obesity were retrieved from the PubMed database, using the combinations of Mesh terms for "Leptin" and "Metabolism".
Results:
Forty-seven randomized and non-randomized controlled trials, dating from 2000 to 2021, were included in the qualitative synthesis.
Discussion and conclusions:
Leptin secretion displays a stabilizing pattern that is more sensitive to a negative energy intake imbalance. Leptin levels influence body weight and fat mass as a pro-homeostasis factor. However, long-term exposure to elevated leptin levels may lead to mental/behavioral disorders related to the feeding and reward systems.
... Most studies address leptin as a potential pharmacological therapy in the control of weight gain and obesity [32,33]. However, the complexity of leptin actions and its differential interactions with other metabolic factors, both in the body and in the brain, requires a deeper understanding of the physiology of leptin in terms of weight gain/loss control [34][35][36][37]. ...
Obesity and being overweight have been described as potential causes of neurological disorders. Leptin, a peptide expressed in fat tissue, importantly participates in energy homeostasis and storage and has recently been identified for its signaling receptors in neuronal circuits of the brain. Aim: To elucidate whether the endogenous modulation of leptin can be a protection against neuropsychiatric disorders. Method: A systematic review was performed in accordance with the PRISMA-P method, and reports of studies containing data on leptin concentrations in healthy individuals with or without obesity were retrieved from the PubMed database, using the combinations of Mesh terms for “Leptin” and “Metabolism”. Results: Forty-seven randomized and non-randomized controlled trials, dating from 2000 to 2021, were included in the qualitative synthesis. Discussion and conclusions: Leptin secretion displays a stabilizing pattern that is more sensitive to a negative energy intake imbalance. Leptin levels influence body weight and fat mass as a pro-homeostasis factor. However, long-term exposure to elevated leptin levels may lead to mental/behavioral disorders related to the feeding and reward systems.
... Metreleptin administration in patients with lipodystrophy can suppress hyperphagia (2,14) and lead to substantial improvement of metabolic abnormalities, including hypertriglyceridemia, hyperglycemia, and insulin resistance (14,15). In GLD, a dramatic decrease in both hypertriglyceridemia and hyperglycemia, as measured by hemoglobin A1c (A1c) after metreleptin treatment has been reported in several studies (16)(17)(18)(19). In PLD, treatment with metreleptin has been associated with a smaller reduction in triglycerides, and conflicting findings have been reported regarding its effects on glycemic control (19)(20)(21)(22). ...
Context
Leptin replacement with metreleptin improves glycemia and hypertriglyceridemia in severely hypoleptinemic patients with Generalized Lipodystrophy (GLD), but its effects are variable in partially leptin-deficient patients with Partial Lipodystrophy (PLD).
Objective
Compare three leptin assays (Study I); identify diagnostic performance of leptin assays to detect responders to metreleptin for each assay (Study II).
Design
Study I: cross-sectional analysis of average bias between leptin assays. Study II: retrospective analysis of diagnostic accuracy of potential leptin cut-points to detect clinical responders to metreleptin.
Setting
National Institutes of Health (NIH); University of Michigan.
Participants and Interventions
Study I: Metreleptin-naïve patients with lipodystrophy (GLD, n=33, PLD, n=67) and healthy volunteers (n=239). Study II: GLD (n=66) and PLD (n=84) patients treated with metreleptin for 12 months.
Outcome Measures
Leptin concentrations by Millipore RIA; Millipore ELISA (MELISA); R&D systems ELISA, (RDELISA). Response to metreleptin therapy was defined as either reduction ≥1.0% in A1c or ≥30% in serum triglycerides.
Results
RDELISA measured 3.0±9.5 ng/mL higher than RIA; MELISA measured 11.0±17.8 and 14.0±19.2 less than RIA and RDELISA, respectively. Leptin by RIA, MELISA, and RDELISA modestly predicted metreleptin response in GLD+PLD (ROC AUC 0.74, 0.69, and 0.71, respectively; p<0.01 for all) with lower predictive power in PLD (ROC AUC 0.63, 0.61 and 0.65, respectively; p>0.05 for all). The only reproducible cut-point identified on sensitivity analyses was RIA leptin 7.2 ng/mL (sensitivity 56%; specificity 78%).
Conclusions
Three common leptin assays are not interchangeable, and a reliable cut-point to select responders to metreleptin was not identified.
