Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span

Abstract

Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan.

Fig. 1.

Obesity and CR regulate health-span by exerting reciprocal, regulatory effects on the immune system. Aberrant elevation of leptin and reduction in ghrelin during obesity may directly regulate immune cell function. On the other hand, an increase in ghrelin and reduction in anorexigenic factors caused by CR may promote immune function and promote longevity.

Fig. 2.

Adipose-immune interactions during obesity. The products derived from the brain and immune system, which regulate obesity and function of these systems, may also be impacted by obesity. The expansion of the adipose organ during obesity and interactions between leukocytes and adipocytes within adipose tissue are also responsible for increased inflammation. This nutrient excess-induced inflammation seen during obesity affects immune function and is responsible for ancillary disease states of obesity, leading to premature death.

Fig. 3.

Hypothetical model for a functional role of AMPK as a central metabolic sensor affecting inflammation and immune function. An increase in AMP concentrations during negative energy balance elicited by CR activates AMPK, and excess energy reserve during obesity inhibits AMPK. Activation of AMPK negatively regulates mTOR, NF-κB, and JNK pathways, thus regulating inflammation. IKKβ, Inhibitor of κB kinase β; ROS, reactive oxygen species; PKC, protein kinase C.

Fig. 4.

Hypothetical model showing the molecular mechanism of AMPK-induced reduction in proinflammatory cytokines. Orexigenic metabolic factors, such as ghrelin, up-regulated during negative energy balance, bind to their specific receptors on immune cells and signal to inhibit NF-κB-mediated inflammation. The phosphorylation of IκB and subsequent translocation of p50 and p65 subunits to the nucleus and NF-κB activation are ATP-dependent events. An increase in intracellular AMP levels during this reaction may lead to activation of AMPK, which may directly block the NF-κB-mediated transcription of proinflammatory cytokines. GHS-R, Growth hormone secretatogue receptor.

Fig. 5.

Increase in adipocytes in the bone marrow microenvironment with age. The femurs of young (2 months) and old (18 months) mice were decalcified and stained using H&E.