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Central and Peripheral Modulators of Appetite and Satiety
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Gabrielle Page-Wilson, Sam Dagogo-Jack
The enthusiasm surrounding leptin’s therapeutic potential for reversing obesity has waned due to its lack of consistent efficacy in obese populations. Nonetheless, the possibility of restoring leptin responsiveness by using it in conjunction with agents like exendin-4 has shown promise in rodents and is a strategy worthy of exploration in human obesity (Muller et al. 2012). Notably, recombinant methionyl human leptin (metreleptin) was recently approved by the U.S. Food and Drug Administration for the treatment of congenital or acquired general lipodystrophy. The currently known metabolic and behavioral effects of leptin are summarized in Table 1.3.
Neuroendocrine Interactions in the Control of Glucose- and Energy Homeostasis
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Unlike insulin resistance, which can be at least partially overcome by further increasing the levels of insulin (58), enhancing the circulating levels of leptin is completely ineffective. Attempts to restore the physiological role of leptin have failed, and the concept of leptin resistance remains poorly understood (59). Recent studies have provided strong evidence that increased circulating levels of leptin might be a driving force for insulin resistance. For example, it has been demonstrated that blocking central leptin signalling in DIO mice restores the ability of the liver to suppress glucose production (60). Consistently, a partial reduction of plasma leptin levels restores hypothalamic leptin sensitivity in obese mice and effectively reduces weight gain and enhances insulin sensitivity (61). Heterozygous whole-body leptin knockout mice and an adipocyte-specific congenital leptin knockout mouse reveal partial leptin deficiency and interestingly protection from DIO. Furthermore, while on the chow diet, glucose tolerance and insulin sensitivity remained unchanged, a marked improvement occurred after mice were fed HFD (62). Reducing leptin levels in DIO mice with a long-acting leptin antagonist (PESLAN) significantly improved glucose tolerance and decreased astro- and microgliosis in the hypothalamus of mice fed a high-fat diet while inducing hyperleptinemia led to the opposite effect suggesting that high levels of leptin promote hypothalamic inflammation (63). In Lepob/ob mice that are extremely leptin sensitive to exogenous leptin, we found that inducing central hyperleptinemia is not sufficient to develop leptin resistance since these mice continued to lose bodyweight and consume less food. However, exposure to HFD immediately arrested the bodyweight reduction induced by hyperleptinemia. Furthermore, HFD reduced the ability of central leptin to improve glucose homeostasis (64). This insufficiency of hyperleptinemia to impair body weight regulation is in line with other studies (65, 66). For instance, in a recent study using transgenic mice where leptin expression was induced by doxycycline to negate developmental impacts, elevating leptin levels during adulthood did not show any effects on body weight gain when mice were fed chow diet (67). In conjunction with HFD feeding, however, increased circulating levels of leptin appear to potentiate the disruption of energy homeostasis leading to increased body weight gain. Some human studies support the concept that hyperleptinemia impairs energy metabolism. For instance, hyperleptinemia is strongly associated with the occurrence of low-grade systemic inflammation and metabolic dysfunction in obese subjects (68). When obese individuals were separated into different groups depending on their baseline leptin levels followed by injection with metreleptin to achieve weight loss, those individuals who had the lowest baseline leptin levels showed the most profound weight loss, suggesting increased leptin sensitivity (69). In contrast, individuals who exhibited higher baseline plasma leptin levels are more prone to regaining body weight lost (70). Individuals who undertook a weight-loss regimen showed reduced levels of leptin but the reduction in leptin did not counteract weight loss; indeed, it was correlated with further weight loss (71).
Effects of metreleptin in patients with lipodystrophy with and without baseline concomitant medication use
Published in Current Medical Research and Opinion, 2021
Kelly Adamski, Keziah Cook, Deepshekhar Gupta, Eric Morris, Edward Tuttle, Emma Carr, Francesco Cremasco, Elaine Cochran, Rebecca J. Brown
Metreleptin is a subcutaneous injection indicated as an adjunct to diet as a replacement therapy for the management of lipodystrophy6. The value of metreleptin was established in a single-arm clinical trial, which achieved its co-primary efficacy endpoints of the actual change from baseline in HbA1c at month 12 and the percent change from baseline in fasting serum triglycerides (TGs) at months 127,8. The regulatory trial provides a comprehensive, long-term assessment of patients treated with metreleptin, spanning 14 years of data collection, with a mean duration of treatment with metreleptin of 5 years7. At the time of publication, metreleptin is approved for the management of metabolic complications associated with lipodystrophy in patients with GL (US, EU, Japan) and PL (EU and Japan)9,10.
ANGPTL3: a novel biomarker and promising therapeutic target
Published in Journal of Drug Targeting, 2019
Shuang Jiang, Guo-Hui Qiu, Neng Zhu, Zhe-Yu Hu, Duan-Fang Liao, Li Qin
Leptin is mainly secreted from the white adipose tissue acting on the hypothalamic regions of the brain which control eating behaviour, thus playing a significant role in maintaining body’s metabolism [41]. It is also reported that leptin can reduce the expression of ANGPTL3. ANGPTL3 mRNA expression in plasma is upregulated in leptin-resistant db/db and leptin-deficient ob/ob mice. The elevation of ANGPTL3 is associated with the increased levels of TG and FFA. In contrast, leptin supplements decrease ANGPTL3 transcription and plasma ANGPTL3 level in ob/ob mice [42,43]. Therefore, the elevated ANGPTL3 level is attributed to the enhancement of plasma TG and FFA concentrations in leptin- or insulin-resistant obesity patients [43]. Furthermore, compared with healthy controls, plasma ANGPTL3 level is higher in patients with lipodystrophy. Metreleptin, as a recombinant human leptin analogue, is approved by the Food and Drug Administration (FDA) in 2014 for the treatment of lipodystrophy. After metreleptin treatment, the levels of ANGPTL3, total cholesterol (TC), TGs, and glycosylated haemoglobin are decreased significantly for the treatment of systemic fat metabolism disorders [44].
Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases
Published in Current Medical Research and Opinion, 2019
Camille Vatier, Marie-Christine Vantyghem, Caroline Storey, Isabelle Jéru, Sophie Christin-Maitre, Bruno Fève, Olivier Lascols, Jacques Beltrand, Jean-Claude Carel, Corinne Vigouroux, Elise Bismuth
Because lipodystrophic syndromes are rare, many physicians are inexperienced in the diagnosis and management of these disorders. Specific, additional diagnostic efforts are thus required in patients presenting with atypical diabetes. A thorough physical examination for fat mass repartition, muscular phenotype, and hepatomegaly is necessary. Standard metabolic exploration for hepatic enzyme levels, hypertriglyceridemia, and insulinemia is also necessary, as is fat mass assessment by DEXA, and evaluation for leptinemia. BSCL can have an unusual presentation, especially in neonates and infants. The symptoms can easily be confused with other metabolic disorders. Although lipodystrophic syndromes are rare, early diagnosis is imperative to facilitate specific management. Metreleptin can be helpful, in addition to diet and other antidiabetic medications, to efficiently control the metabolic complications of congenital generalized lipodystrophy.