Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?

Abstract

The adipocyte-derived ‘satiety promoting’ hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an ‘adipostat’, whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its ‘anti-obesity’ effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin’s metabolic effects while retaining leptin’s permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.

Mechanisms of leptin-induced endothelial dysfunction

“…Systemically, leptin receptor is a type l cytokine receptor with long and short isoforms but is consistent in structural form as a tyrosine kinase transmembrane receptor. Leptin binding to its receptor induces phosphorylation of Janus kinase 2 (JAK2), activating phosphotyrosines that serve as binding sites for various intracellular signaling pathways [1]. Protein tyrosine phosphatase 1B (PTP1B) inhibits the activation of leptin receptor signaling by preventing the JAK2 phosphorylation.…”

Highly recruited brown adipose tissue does not in itself protect against obesity

“…This is generally discussed as indicating the existence of a mechanism, referred to as an adipostat or a lipostat. Functionally, this is ascribed to the brain being informed of the status of the body's energy reserves and thus taking adequate countermeasures if body weight/body energy reserves deviate from desired levels [ [41] , [42] , [43] , [44] , [45] ]. Leptin is generally thought to be the (main) conveyer of this information from the periphery to the brain [ 46 ], but there are indications that other systems may be involved [ [47] , [48] , [49] , [50] ].…”

Adipokinesand Ghrelin Rolein Regulation of Ovarian Function in Obesity

“…Несмотря на то что механизмы, с помощью которых лептин регулирует стероидогенез, до конца не изучены, известно о возможном участии сигнальных путей ERK1/2, PI3k-Akt и CRTC1, способных к модуляции репродуктивной функции в гранулезных клетках. Также открыты негативные регуляторы сигнализации лептина (SOCS3, PTP1B, PTPe и TCPTP), в основном нацеленные на сигнализацию пути STAT3, который, однако, влияет на метаболическую функцию более ощутимо, чем на репродуктивную [35].…”