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.

Keywords: adiposity; brown adipose tissue; hyperleptinaemia; leptin; leptin-resistance; obesity; thermogenesis.

Figure 2

Schematic overview summarising obesity-associated hyperleptinaemia, leptin resistance and leptin deficiency.

Figure 1

Possible relationship between circulating leptin levels and leptin sensitivity in lean (A) and obese (B) subjects. ↑ increase, ↓ decrease; + activation, − inhibition.