Physiological regulation of leptin as an integrative signal of reproductive readiness

Species survival depends on successful reproduction, which in turn is influenced by both environmental and physiological factors. Among these, food availability and stored energy reserves are considered to be critical influences on mammalian reproduction due to the high energy demands of pregnancy, lactation and caring for offspring. However, other factors also play a role in signaling to the brain whether conditions are optimal for successful reproduction, such as seasonal and circadian cues, immune stress, and psychosocial stress. The reproductive control center in the brain—the hypothalamic gonadotropin-releasing hormone (GnRH) neuronal network—must therefore receive signals about nutritional status, environmental conditions, and mental and physical wellbeing. One of these signals is the adipose-derived hormone leptin, most known for its role in regulating appetite and body weight by promoting a starvation signal when its concentrations are low or downstream signaling is impaired. Circulating leptin concentration positively correlates with body adiposity, and thereby relays information about long-term body energy stores to the brain. Low leptin levels, which generally reflect low adiposity and inadequate energy availability, are associated with reproductive suppression. Thus, leptin is considered a critical permissive signal in the metabolic control of fertility.

Not surprisingly, the complete absence of leptin signaling (usually only seen in genetic mutants) causes overeating, obesity and infertility. Interestingly, it also causes sleep-disordered breathing [1], circadian disruption [2], impaired immunity [3,4], increased anxiety-like behaviors [5] and other mood disorders [6] in humans and animals. While genetic leptin or leptin receptor (LepR) deficiency is rare, low leptin levels (hypoleptinemia), impairments to leptin's diurnal and ultradian rhythmicity, and leptin resistance can likewise cause physiological disruptions to normal function. Although the most significant correlate of circulating leptin levels is adiposity, leptin production is also acutely influenced by other factors, such as fasting, perceived stress, infection and inflammation, and circadian cues, among others. Therefore, leptin's modulatory impact on the GnRH neuronal network not only serves to relay information about adiposity and energy availability, but also appears to act as a key integrative signal that communicates a general message about whether current conditions are favorable for reproduction. This review will discuss the different mechanisms by which leptin serves to relay information about metabolic, psychological, environmental and immune conditions to the central governors of reproductive function—the GnRH neurons (see Figure. 1).

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