Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

Abstract

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

“…Alterations in their levels are well-characterised indicators of AT dysfunction in obesity [ 29 , 53 ]. Leptin plays a key role in regulating glucose homeostasis, increasing energy expenditure and reducing food intake and body weight [ 54 , 55 ]. Animal models lacking leptin or the leptin receptor ( ob/ob and db/db mice, respectively) show weight gain, hyperinsulinemia, insulin resistance, and impaired glucose homeostasis [ 56 ].…”

Leptin Protein Expression and Promoter Methylation in Ovarian Cancer: A Strong Prognostic Value with Theranostic Promises

“…Remarkably, women with a higher BMI reported having symptoms for a longer time before being diagnosed with OC [ 53 ]. In this context, leptin is a key adipocyte-derived factor involved in energy balance, appetite regulation, nutrient intake, energy balance, metabolic homeostasis, adipose tissue expansion, obesogenic pathways, and central nervous insensibility to leptin (loss of responsiveness, “type 2 obesity”) [ 54 , 55 ]. Moreover, in vitro studies reported that high levels of LEP stimulate proliferation, cell migration, invasion and inhibit apoptosis of OC cells [ 56 , 57 , 58 ].…”

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity

“…Leptin is a hormone secreted by adipose cells, and its receptor is expressed both centrally in the hypothalamus and peripherally in several tissue [75,76]. Leptin can also be expressed in the lung by adipose-like lipofibroblasts and has a known role in regulating pulmonary surfactant production [77].…”

“…Leptin can also be expressed in the lung by adipose-like lipofibroblasts and has a known role in regulating pulmonary surfactant production [77]. The central action of leptin promotes satiety and body weight reduction, while its action on adipose tissue increases glucose utilisation and lipolysis [75,76]. Paradoxically, hyperleptinaemia is common in obese subjects, and circulating levels of leptin are proportional to adipose tissue mass [78].…”

“…Paradoxically, hyperleptinaemia is common in obese subjects, and circulating levels of leptin are proportional to adipose tissue mass [78]. However, due to a feedback mechanism regulated by cytokine signalling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B), persistent leptin stimulation in obesity can lead to impaired leptin signalling and subsequent inability to mediate its anorexigenic effects, a state referred as 'leptin resistance' [76]. Therefore, we hypothesised that enhanced circulating leptin concentrations, particularly in subjects with obesity or type 2 diabetes mellitus, may contribute to several comorbidities, such as renal injury or cardiovascular disease [79,80].…”