Improving reproductive health: Reducing Neuroinflammation and Obesity. Pt.2

The crosstalk between the gastrointestinal hormones that promote metabolic cues is integrated by the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY) neurons localized in the hypothalamus. Furthermore, these metabolic cues determine orexin synthesis and secretion by the hypothalamus, regulating food intake or satiety. In addition, these neurons controlling capacities depend on the sensory levels of hormones like leptin and insulin. Also, POMC and NPY play a crucial role by communicating metabolic status to neurons involved in reproduction, such as GnRH and Kisspeptin neurons.

POMC and reproductive health

POMC promotes the sensation of satiety and regulates food consumption by diminishing hunger cues. Also, it is expressed in neurons located in the arcuate nucleus (ARC) of the mediobasal hypothalamus. When POMC is cleaved, it releases anorexigenic a-MSH melanocortin and orexigenic b- endorphin (b-END) opioid peptide. An increase in leptin levels triggers this anorexigenic precursor, resulting in reduced food intake and increased energy expenditure. 

In rat brains, POMC neurons are closely ubicated to GnRH neurons, where they can exchange information or possibly determine each other functions. Indeed, the secretion of a-MSH activates GnRH neurons resulting in LH secretion. On the other hand, the secretion of b-END has a close association with the inhibition of GnRH neurons and a reduction in LG secretion.

NPY

Neuropeptide Y is an orexigenic neuropeptide synthesized by the ARC neurons in the hypothalamus. This neuropeptide activates in the presence of ghrelin, a hormone secreted by the stomach and intestine that promotes a hunger signal that stimulates NPY and increases food intake. In addition, NPY synthesizes g-aminobutyric acid (GABA), which has the function of inhibiting POMC neurons. Another essential factor to NPY functions is its connection with Agouti-related protein (AgRP), commonly coexpressed in NPY.

The reproductive and energetic circuitry is not yet elucidated, but recent animal models have found interesting effects between these mechanisms. Animal studies using ovariectomized rhesus macaques reported that the administration of NPY stimulated the GnRH release when localized. On the other hand, the intracerebroventricular administration of NPY inhibited LH pulses. 

Metabolic signals: insulin, adiponectin, and leptin

Insulin is an anabolic hormone that regulates cell growth and metabolism by glucose uptake. Most animal studies use mice with brain-specific knockdown insulin receptors, which has a consistent result: infertility due to low levels of LH. Furthermore, diabetic sheep intervened with insulin showed a rise in LH pulsatility. On the other hand, it has been reported that GnRH neurons have insulin receptors that do not alter pubertal development when knocked down. Therefore, several studies concluded that insulin might interact with GnRH at the pituitary level.

Adiponectin

Adiponectin is known for its anti-inflammatory and protective effects. It is synthesized and secreted by the adipose tissue, and its presence coincides with an increase in insulin sensitivity, energy expenditure, and reduction of liver gluconeogenesis. Furthermore, higher levels of adiponectin negatively correlate with BMI. Also, higher adiponectin levels are reported in women than in men. In animal models, female adiponectin null mice displayed reproductive dysfunction, reduced retrieval of oocytes, disrupted estrous cycle. Also, this study found a high number of atretic follicles and impaired late folliculogenesis with lower estradiol and FSH concentration but elevated LH and testosterone. 

Leptin

Adipocytes also secrete leptin as a satiety factor to regulate food intake by creating a signal that travels to the brain. In addition, it seems to have a strong connection with reproductive health since ob/ob mice, both male and female, are infertile. However, when these mice are treated with leptin, it restores their reproduction ability. 

Another critical factor seen in this animal model is that ob/ob mice show a delayed onset puberty and blocked the estradiol-induced LH surge.

It is clear that hormone balance hot only depends on the production, transportation, sensitivity, and detoxification pathways but also depends on the environment our body provides for these mechanisms. The intricate circuitry of the HPG axis allows a neuronal interaction that delays, promotes, or inhibits reproduction mechanisms. – Ana Paola Rodríguez Arciniega, MS.

References:

Lainez, N. M., & Coss, D. (2019). Obesity, Neuroinflammation, and Reproductive Function. Endocrinology, 160(11), 2719–2736. doi.org/10.1210/en.2019-00487

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