Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Abstract

Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4 + T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3 + ) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response.immune system | sirtuins H ypothalamic Agouti-related peptide-expressing (AgRP) neurons are mandatory for feeding and survival (1, 2) and they mediate effects of the hystone deacetylase Sirtuin 1 (Sirt1) on energy metabolism (3, 4). Behavioral and metabolic adaptations to low energy availability are enabled by AgRP neurons, but it is unknown whether these neurons are involved in the regulation of other tissue functions key to survival, such as adaptive immune responses. Sirtuins are NAD + -dependent class-III deacetylases that are highly conserved across species (5). Nutrient deprivation up-regulates Sirt1 in several tissues (6, 7), which is important for the metabolic shift that occurs during negative energy balance (8), a metabolic state in which energy expenditure is higher than energy intake. Evidence suggests that the effects of sirtuins may mediate the beneficial effects of calorie restriction, the only known physiological intervention that promotes a longer, healthier lifespan across species (9-14). However, the site of action of sirtuins in these physiological processes remains ill-defined.The CNS was previously recognized as an immune-privileged site with lack of immunosurveillance. However, accumulating evidence has shown that a mutual interaction between the immune system and CNS exists both in physiological and pathological situations (15). The CNS influences and controls the immune system at least partly through the autonomic nervous system (15). Lymphocytes express the receptors for different neurotransmitters, which enable the brain to properly coordinate the immune system and to maintain the homeostasis of the whole body by responding to environmental changes, such as infections, in an appropriate manner. In this context, we and others have shown that nutritional status can affect T helper 1 (Th1) proinflammatory immune responses through a series of adipose-tissue-derived hormones including leptin, which mediates its effects on immune cells either directly by activating leptin receptors on T cells or indirectly by its effect on autonomic nervous system.

Age-dependent dysregulation of innate immunity

“…Another non-immune contribution to the inflammatory environment is the neuroendocrine axis linking the central nervous system to the periphery via the hypothalamus. Knockdown of the histone deacetylase Sirtuin 1 in hypothalamic neurons induced a pro-inflammatory activated state in peripheral CD4 + T cells 137 . Indeed, recent studies indicate that mammalian lifespan itself may be linked to an NF-κB-dependent inflammatory state in the hypothalamus, which occurs in aged mice and is linked to decreases in gonadotropin releasing hormone 138 .…”

SIRT1 in Neurodevelopment and Brain Senescence

“…Other functions attributed to hypothalamic AgRP neurons including regulation of adaptive immunity, exploratory drive and response to cocaine are also altered in mice when SIRT1 is ablated in these cells (Dietrich et al, 2012; Matarese et al, 2013). Immunologic changes are caused by disinhibition of POMC neurons that project to the thoracic spinal cord, increasing sympathetic tone.…”

“…Immunologic changes are caused by disinhibition of POMC neurons that project to the thoracic spinal cord, increasing sympathetic tone. Deletion of SIRT1 in AgRP neurons creates a proinflammatory environment, with enhanced effector T-cell activity and decreased regulatory T-cell function (Matarese et al, 2013). AgRP neurons also innervate the ventral tegmental area (VTA) of the midbrain, and SIRT1 deletion results in higher levels of dopamine in the forebrain and facilitates long-term potentiation in a spike-timing dependent protocol (Dietrich et al, 2012).…”

“…SIRT1 also regulates activity and body temperature in the dorsomedial and lateral hypothalamus (Satoh et al, 2010). In arcuate nucleus, SIRT1 modulates appetite, adaptive immunity and reward circuitry (Dietrich et al, 2010; Matarese et al, 2013). In the superschiasmatic nucleus of the hypothalamus, SIRT1 levels decrease with aging, affecting the activity pattern and circadian period.…”

Acute hypothalamic administration of L-arginine increases feed intake in rats

“…Food intake is controlled by complex neural systems that act receiving signs from the digestive system, passing through the adipose tissue, and reaching the CNS 5 . The hypothalamus is considered one of the main regions of the CNS that is directly related to appetite and the various hormonal and neural mechanisms by which the brain is informed about the availability of ingested, stored, and consumed nutrients [6][7][8] . Food control mechanisms are controlled by the hypothalamus function through the integration of multiple sensory signals that activate or deactivate food search behaviors.…”