Ghrelin Receptor and Inflammaging

Ghrelin is related to the hunger response, but has a very broad range of influences on many tissues and systems, including immune system activities. Inflammaging is the name given to the inflammation-focused view of the characteristic decline and dysfunction of the immune system with aging. While increased levels of inflammation occur for everyone due to immune system aging, those people who allow themselves to become overweight suffer a greater level of chronic inflammation, driven by the way in which metabolically active visceral fat tissue provokes immune activation. The research here joins all of these dots, and the scientists involved demonstrate that removing the ghrelin receptor in mice can suppress the influence of fat tissue on chronic inflammation:

"To date, ghrelin is the only known appetite-stimulating hormone. The pharmaceutical industry has been calling ghrelin 'the key to obesity' since its discovery. We investigated the impact of ghrelin signaling on adipose tissue macrophages, in order to understand the role of ghrelin signaling in obesity." Hunger stimulates ghrelin in the gut, which activates brain regions where the ghrelin receptor, growth hormone secretagogue receptor, or GHS-R, is highly expressed, triggering the hunger sensation. Ghrelin enhances appetite and increases weight gain, promoting obesity and consequent insulin resistance.

Obesity, in essence, is a condition characterized by low-grade chronic inflammation in adipose tissues. Adipose tissue serves as a major endocrine organ, secreting various hormones and cytokines which play crucial roles in normal metabolism and obesity-associated dysfunctions. Adipose tissue macrophages, or ATMs, are a major mediator of inflammation in adipose tissues, which are closely linked to insulin resistance. Macrophages are a type of white blood cells that surround and digest microbes, pathogens and other foreign substances. "Macrophages are a major mediator of inflammation in the body. Increased macrophage infiltration in adipose tissues has been shown to positively correlate with age-associated metabolic complications, neurodegenerative diseases and cardiovascular diseases."

ATMs consist of two subsets - pro-inflammatory M1 and anti-inflammatory M2. M1-like macrophages are associated with an obese and insulin-resistant state, while M2-like macrophages are associated with a lean and insulin-sensitive state. M1-like macrophages release pro-inflammatory cytokines to inhibit insulin action in the tissues. On the other hand, M2-like macrophages release anti-inflammatory cytokines. "We have found that the GHS-R functions as a key regulator of age-associated adipose tissue inflammation. The removal of GHS-R shifts macrophages toward an anti-inflammatory state." Aging is commonly accompanied by increased fat mass and chronic low-grade inflammation, so concurrences of obesity and insulin resistance become significantly greater as people get older.

GHS-R global null mice - with the GHS-R removed in all cell types - showed a macrophage profile shifted toward the anti-inflammatory M2, exhibiting a healthier lean and insulin-sensitive phenotype. "Old mice with GHS-R deletion showed a reduction in macrophage infiltration, M1/M2 ratio and pro-inflammatory cytokine production in adipose tissues." The new findings suggest suppressing the ghrelin receptor may serve as a new therapeutic strategy for inflammation and obesity in aging. The study indicates the ghrelin receptor plays an important role in macrophages, which can have profound implications on obesity and insulin resistance. Current research using global null mice cannot determine whether the phenotype is resulted in by the effect of GHS-R in macrophages alone, however. Scientists must determine the macrophage-specific effects of GHS-R, and understand precisely how ghrelin signaling works, in order to avoid unintended side effects. The researchers are now developing new mouse models which would enable them to delete GHS-R selectively in macrophages.


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