After learning the intricacies between neuronal signaling and gastrointestinal hormonal stimulation, we now understand how they influence each other. However, we need to take into account the environment in which these processes are taking place. Is the patient overweight or obese? Is there a chance that adipose-induced inflammation influences reproductive health? The neuroinflammation promoted by a high-fat diet is strongly associated with a detrimental effect on reproductive health.

Obesity-induced macrophage infiltration

A high-fat diet and sedentary lifestyle associate with higher adipose tissue levels, creating an inflammatory milieu known as chronic inflammation. Indeed, an increase in adipose tissue is followed by a progressive infiltration of macrophages, resulting in a vicious circle leading up increased levels of pro-inflammatory cytokine production. 

Furthermore, visceral fat has a higher concentration of macrophages than subcutaneous adipose tissue. The activation of macrophages is stimulated by adipocyte growth and the production of monocyte chemoattractant protein-1 (MCP-1 or CCL1 chemokine). This process lures monocytes and leads to macrophage activation. In addition, elevated leptin concentrations lead to macrophage accumulation in the adipose tissue and the adhesion of macrophages to endothelial cells. However, the patient’s body composition plays a determinant role in the activation of macrophages. Studies show that macrophages of lean individuals show an M2 phenotype which secretes anti-inflammatory cytokines. On the contrary, those obese individuals showed macrophage-induced pro-inflammatory markers like TNF-a, IL-6, and IL-1B.

Besides this mechanism, the recruitment of macrophages at the organs had an impactful effect on health. For instance, macrophage recruitment in the liver coincides with insulin resistance. A recent study shows that the recruitment of macrophages in the brain has been localized in the hypothalamus of obese male mice. In addition, this study reported a higher macrophage recruitment rate in male mice than in female mice. This last finding may explain why males have a higher propensity to obesity-mediated neuroinflammation.

How to target obesity?

Functional medicine treatment starts on detecting the issue.  Therefore, anthropometry and the determination of our patient’s body composition are essential to plan the treatment. With the use of top-notch technology, with InBody 770 we can measure fat deposits, water content, and muscles mass and follow up the improvements.

Brain immunity and reproduction

Neuroinflammation tightly associates with the ingestion of a high-fat diet and the rise of systemic inflammation. Adipose-associated inflammation contributes to the apparition of diseases like dementia or cerebral ischemia. Furthermore, the brain’s resident immune cells, microglia, have the function of maintaining standard circuitry and good plasticity by cropping synapses. Microglial cells activate in response to injury, disease, infection by engulfing damaged synapses and secreting cytokines, which might recruit peripheral immune cells. These mechanisms occur when neurons communicate via fractalkine and its receptor, CX3CR1, with microglial cells. 

However, obesity-induced inflammation causes two significant changes in the structure and function of microglial cells affecting reductive health. Indeed, obesity alters the expression of fractalkine and CX3CR1 inhibiting important neuron-microglial communication. The second change is microglial activation to the M1 phenotype associate with the expression of IL-1β, IL-6, IL-8, and TNF-α. This mechanism is activated due to a high concentration of fatty tissue, specifically visceral fat accumulation. 

Blood-brain barrier obesity-induced permeability 

The blood-brain barrier (BBB) is composed of endothelial cells that express tight junction proteins, interspersed pericytes embedded in the basement membrane, and perivascular space bordered by astrocytic endfeet of the glia limitans. The BBB properties conferred an immune privilege to the CNS until BBB permeability became more common as the obesity pandemic evolved.

There are several theories of how obesity and BBB permeability interact with the inhibition of reproductive mechanisms. One of them being the increase of cytokine levels promoted by obesity or HFD. Furthermore, this mechanism activates the gene expression of glial cells and neurons located near the fenestrated capillaries. Consequently, microglial cells activate and commence the recruitment of macrophages and increase the synthesis and release of cytokines. 

Obesity is a multifactorial disease that affects more than 30% of the adult population in the United States. Despite being a significant public health concern due to its harmful effects o cardiovascular and metabolic health, it also results in reproductive complications. Furthermore, the interplay between hunger cues, gastrointestinal hormones, pro-inflammatory cytokines, and neuronal circuitry implies that reproductive health is not only a reproductive issue. Indeed, reproductive issues should be treated with a multi-faceted treatment that includes anti-inflammatory measures to decrease cytokine levels, weight management, and antioxidant supplementation. – 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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