The Science of Health Disparities Research

Figure 2.1 Schematic representation of the concept of Allostatic Load: (a) Graphic illustration of conceptual linkages between allostasis and environmental stress and chronic disease; (b) Graphic representation of the role and components of allostatic load over the life course illustrating influences of biological embedding, neuronal plasticity, and cumulative “wear and tear” in response to environmental stressors.

However, persistent or chronic overuse of the stress response systems leads to cumulative “wear and tear,” or cellular, physiological, cognitive, and emotional dysfunction, that eventually becomes maladaptive. Over time, this “weathering,” the disproportionate deterioration as a result of cumulative wear and tear that begins at an earlier age and is patterned by race, can result in disease [6]. The chronic conditions or diseases that result from persistent allostasis are referred to as allostatic load ( Figure 2.1b) [3].

Allostatic load provides a conceptual bridge to understanding how the basic cellular and molecular biology underlying human physiology interacts with behavior and environmental exposures to affect health. Furthermore, it provides a framework to help us understand how certain aspects of human lived experience (e.g., social isolation and racism) and environmental exposure can become “embedded” or “baked in” to influence behavioral patterns and biological events across the life course [3]. The central thesis of allostatic load is that cumulative chronic stress may “get under the skin,” so that past events, occurring as distantly as early childhood or even prenatally, can have persistent effects far into adulthood [7]. These concepts form the foundation that supports how differences in societal experience can be the root cause of disparities in health outcome [8]. The concept of allostatic load enables an exploration of gene‐environment and epigenetic interactions that will ultimately provide insights into intervention.

In summary, allostasis and the influence of allostatic load occur and accumulate throughout life with consequences that ultimately result in chronic physical, emotional, and cognitive decline [3]. Understanding the forces through which societal, behavioral, and environmental determinants combine with biological susceptibility will be the subject of this chapter.

The HPA axis wields a pervasive influence on health behaviors, including diet, physical activity, and sleep [4, 5]. The paraventricular nucleus (PVN) is a core component of the HPA axis. In response to stress, its neurons produce corticotropin releasing factor (CRF) to stimulate release of pituitary adrenal corticotropic hormone (ACTH), which stimulates production of glucocorticoids (predominantly cortisol) from the adrenal cortex ( Figure 2.2) [4, 5]. The net result of the release of circulating cortisol is to mobilize energy through gluconeogenesis, cause peripheral inhibition of glucose and amino acid uptake, and impair or blunt the immune inflammatory response [5]. The result is a rapid increase in blood glucose that will persist under conditions of chronic stress. Cortisol also has significant influence on the central nervous system through feedback inhibition of pituitary ACTH secretion and production of CRF from the PVN, in addition to significant influence on neurogenesis in the amygdala, hippocampus, and mesocorticolimbic regions ( Figure 2.2).

Figure 2.2 Schematic presentation of stress pathway outputs and inputs to the hypothalamic‐pituitary‐adrenal (HPA) axis in response to stress. NE, norepinephrine; CRF, corticotropin releasing factor; PVN, paraventricular nucleus; ACTH, adreno‐corticotropin.

Source: Derived in part from Spencer and Deak [9].

CRF also acts at the level of the locus coeruleus (LC) to potentiate the secretion of norepinephrine (NE), which works in combination with cortisol to enhance consolidation and retrieval of highly emotional events through their combined influence on neurogenesis in the hippocampus, amygdala, and the mesocorticolimbic system ( Figure 2.2) [3]. LC‐derived NE also enhances peripheral levels of NE through stimulation of the adrenal medulla, resulting in significant changes in the cardiovascular, pulmonary, renal, gastrointestinal, immune, and hepatic tissues [4, 5].

Multiple nuclei within the hypothalamus are involved in complex gating and signaling that result from an intricate mixture of feedback and feed forward involving signals that originate in the complex neurotransmitter and neuroendocrine systems. Often, these interactions involve feedback communication amongst nuclei and signaling molecules from the periphery that indicate nutrient availability ( Figure 2.3) [4, 5]. Following a meal, the two major harbingers of nutrient availability, leptin and insulin, play a major role in driving the signaling cascade in the hypothalamus ( Figure 2.3) [10]. Elevation of blood glucose levels following a meal results in the activation and secretion of insulin from the beta‐islet cells of the pancreas. This occurs in concert with the leptin secretion from adipose tissue, which conveys the signal that energy is available for storage. The arcuate nucleus of the hypothalamus has receptors for both insulin and leptin and responds differently depending on which region of the arcuate receives input ( Figure 2.3). Leptin and insulin repress signaling from neurons of the arcuate that produce the orexigenic agouti‐related peptide (AgRP) and neuropeptide Y (NPY), each of which functions to repress neurons in the PVN responsible for producing anorexigenic thyrotropin releasing hormone (TRH), and CRF. AgRP and NPY also stimulate neurons in the lateral hypothalamus (LH) that produce the orexigenic orexin and the orexigenic and anti‐thermogenic melanin concentrating hormone (MCH) [5, 11]. The net effect of leptin and insulin on AgRP‐ and NPY‐producing neurons is the repression of hunger. In contrast, the function of leptin and insulin on arcuate neurons is to stimulate the expression of anorexigenic pro‐opiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). POMC‐ and CART‐active neurons in the PVN express anorexigenic and thermogenic TRH and CRH, while repression neurons in the LH express orexigenic orexin and MCH. Therefore, in contrast to AgRP and NPY, POMC and CART repress hunger. Thus AgRP/NPY and POMC/CART have significant influence on modulating feeding, nutrient sensing, and the flux of signaling through the HPA axis [11, 12]. Finally, the hypothalamus is subject to modulation by local inflammatory events. Studies have shown that normal physiological control of feeding by the hypothalamus can be disrupted by local inflammation, some of which is influenced by high levels of dietary long chain fatty acids (LCFA) [4, 11]. This local inflammation blunts the response of the hypothalamus to leptin and insulin, thus implicating a role for inflammation in the evolution of obesity ( Figure 2.3) [11].

Figure 2.3 Schematic representation of pathways important in hypothalamic control of energy balance and sleep. VLPO, ventrolaterol preoptic nucleus; DMH, dorsomedial hypothalamus; TRH, thyrotropin releasing hormone; CRF, corticotrophin releasing factor; PVN, paraventricular nucleus; SCN, suprachiasmic nucleus; LH, lateral hypothalamus; HPA, hypothalamus‐pituitary‐adrenal axis; AgRP, agouti‐related peptide; NPY, neuropeptide Y; POMC, pro‐opiomelanocortin; CART, cocaine and amphetamine related transcript; MCH, melanin‐concentrating hormone; TNF‐α, tumor necrosis factor alpha; IL1‐β, interleukin 1 beta; IL‐6, interleukin‐6; LCFA, long chain fatty acids.