OBESITY 2.3. Preventing Chronic Disease: July 2009: 09_0011

SPECIAL TOPIC
The Effect of Neurohormonal Factors, Epigenetic Factors, and Gut Microbiota on Risk of Obesity

TABLE OF CONTENTS
• Abstract
• Introduction
• Neurohormonal Controls
• Epigenetics
• Gut Microbiota
• Conclusion
• Author Information
• References

Matthew A. Haemer, MD; Terry T. Huang, PhD, MPH; Stephen R. Daniels, MD, PhD
Suggested citation for this article: Haemer MA, Huang TT, Daniels SR. The effect of neurohormonal factors, epigenetic factors, and gut microbiota on risk of obesity. Prev Chronic Dis 2009;6(3). http://www.cdc.gov/pcd/issues/2009/jul/09_0011.htm. Accessed [date].

Abstract
Molecular, cellular, and epidemiologic findings suggest that neurohormonal, epigenetic, and microbiologic mechanisms may influence risk for obesity by interacting with socioenvironmental factors. Homeostatic and nonhomeostatic neural controls of energy predispose people to obesity, and this predisposition may be exaggerated by the influence of media, marketing, and sleep patterns. Epigenetic gene regulation may account for the influence of modifiable early life or maternal exposures on obesity risk. Alterations in gut flora caused by infant feeding practices or later diet may influence the absorption and storage of energy. Further exploration of how these molecular-cellular mechanisms might increase obesity risk in response to modifiable socioeconomic factors requires the partnership of laboratory and public health researchers.

Introduction
We describe components of a novel paradigm for obesity-related research and public health interventions that are designed to generate cross-disciplinary hypotheses that account for multiple levels of causation from molecular to societal. The goals of this approach are to understand the causal pathways leading to patterns of obesity in populations and to identify where interventions that can broadly affect the population can be implemented (1). Our focus is on the mechanisms that may be useful for understanding how socioenvironmental factors interact with biological processes to affect energy balance. We review neurohormonal controls, epigenetics, and microbiologic mechanisms in gut flora that may influence risk for obesity.

Neurohormonal Controls
Homeostatic controls
The complex neurohormonal systems controlling weight and adiposity can be categorized as either homeostatic or nonhomeostatic (2). Parsimonious homeostatic mechanisms provided a survival advantage to people faced with periodic starvation. Organisms that could consume, store, and conserve energy efficiently were likely to survive and reproduce (3). Although evolution may have selected against extreme adiposity (4), the negative feedback signals against excess intake are insufficient to maintain normal body weight for most humans who have easy access to palatable, calorie-dense foods (5).

When provided a diet high in calories, animals prone to obesity rapidly increase fat stores (2). Furthermore, when obese rats lose weight or have their calorie intake restricted, they mount the same neurohormonal drive as do lean rats to increase intake and decrease energy expenditure, effectively defending obesity (6,7). After weight loss, the average resting energy expenditure of obese people is markedly and persistently reduced (8). These factors are blamed for the weight regain that occurs in approximately 80% to 90% of obese people who have lost weight (8,9).

A complex interplay of neurotransmitters, hormones, and metabolites regulates food intake in the brain. Metabolic sensing neurons of the hypothalamus and other brain areas respond to signals of energy intake, demand, or storage including circulating glucose, leptin from adipocytes, insulin, ghrelin from the stomach, adrenal steroids, polypeptide YY from the intestines, fatty acids, ketones, lactate, vagal nerve afferents, and intrinsic neurotransmitters (5). Hypothalamic neurons release neurotransmitters that activate either catabolic processes (eg, a-melanocyte-stimulating hormone [a-MSH], cocaine- and amphetamine-regulated transcript [CART], corticotropin-releasing hormone [CRH]) or anabolic processes (eg, neuropeptide Y [NPY], agouti-related protein [AGRP], orexins) (10). Hypothalamic neurons signal broadly to the pituitary, brainstem, midbrain, and forebrain. These pathways regulating energy intake and expenditure have been demonstrated experimentally in animal models and through functional neuroimaging in humans (11).

The interplay between the sympathetic nervous system and leptin signaling is an example of neurohormonal protection of adiposity. With calorie restriction, sympathetic activation releases glucose from glycogen stores and fatty acids from adipose tissue. Adipose tissue responds to sympathetic activity by markedly decreasing leptin production, which decreases resting energy expenditure and increases appetite to replenish fat stores (2). Some rare human obesity syndromes are associated with single gene defects within homeostatic pathways, including leptin deficiency, leptin receptor defect, pro-opiomelanocortin (POMC) deficit leading to impaired a-MSH production, and a-MSH receptor defects (12).

Nonhomeostatic controls
Nonhomeostatic systems promote excess weight gain through responses to the reward properties of food and psychosocial factors associated with eating (5). When a palatable and calorically dense diet is provided, rats eat far beyond limits of homeostasis and develop extreme levels of obesity, even rats predisposed to leanness (13). The more palatable the diet, the higher the degree of obesity and the longer it is sustained (13).

The organization and function of the human brain is a reflection that throughout all but the most recent evolutionary history, obtaining food was a difficult task. Complex pathways record past context and the expectation of reward (14). Reward properties of foods (the stimuli that augment the drive to obtain foods) mediate “liking” by action at opioid receptors and “wanting” by action at dopaminergic receptors. Both of these receptors also mediate addiction (4). Metabolic signals modify the sensing thresholds for food-related stimuli, food-seeking behavior, and reward signals (4). Chronic stress enhances the reward value of foods (15). Although the subcortical areas contribute to subconscious drives for intake, the cortical areas integrate these underlying signals with learned motivational cues. These cues can drive intake well beyond subcortical demands of energy needs (16). Overall, the drive to eat is the result of complex, redundant systems that protect against starvation, but the systems are grossly mismatched to the food and activity environment of the developed world (17).

Implications of neurohormonal mechanisms for obesity and public health
The potency of homeostatic and nonhomeostatic forces that promote weight gain and prevent weight loss make clear the value of obesity prevention, especially considering the cost and difficulty of obesity treatment. Many socioenvironmental factors interact with the neurologic drivers of intake, so identifying and intervening on modifiable levels to prevent obesity is a challenging task.

Sleep may play a role in maintaining proper energy balance by influencing neurohormonal controls (18). A meta-analysis of 30 cross-sectional studies through early 2008 found an odds ratio for obesity of 1.89 in children with short duration of sleep and 1.55 in adults with short duration of sleep (19). More recently published longitudinal studies, one with 32 years of follow-up from birth, also found that shorter sleep times in childhood were significantly associated with increased body mass index (20,21). Experimental studies of sleep deprivation show increased hunger and appetite associated with neurohormonal mechanisms that promote intake: decreased levels of leptin, increased levels of ghrelin, increased sympathetic tone, and increased cortisol (22). Nonhormonal effects of short sleep, such as fatigue and decreased volitional energy expenditure, may also play a role in the association between sleep and obesity. Debate remains about the strength of the evidence that poor sleep causes obesity, and interventions to decrease obesity by increasing sleep have yet to be reported (23).

Media exposure and food marketing either overpower homeostatic negative feedback or strongly amplify nonhomeostatic drivers of intake. Distracting stimuli, such as television viewing while eating, strongly increase intake, possibly by interfering with neural signals of satiety (24). In a controlled experiment, viewing children’s food advertisements caused children to eat much larger portions of snack foods compared to children who watched nonfood advertisements, and the effect was significantly larger on obese children than on normal-weight children (25). Marketing often seeks to influence the emotional responses to food (26) and succeeds in altering the perceived reward value of foods (27). Most food advertisements targeting preschool children involve fast-food restaurants or sweetened cereals. These advertisements associate the products with fun and happiness in an attempt to create long-term customers through positive emotional associations with the product (28). The food industry targets children at stages of development critical to establishing future eating habits (28).

Analysis by the National Bureau of Economic Research estimated that eliminating fast-food restaurant advertising to children would reduce the prevalence of obesity by 18% (29). Some governments have restricted television advertising of food products to children, and some advertisers have voluntarily restricted advertisements (30). However, the recent proliferation of other digital media sources, including cell phones, mobile music devices, broadband video, instant messaging, videogames, and virtual worlds, has created a “marketing ecosystem” for advertisement of food (31,32), and the influence of marketing on intake may become more pervasive in the future.

Epigenetics
Studies searching for determinants of risks for obesity and cardiovascular disease have found that genetics (33,34) and behavioral exposures (35) explain only part of the risk. Epigenetic mechanisms describe environment-gene interactions that may explain some residual risk. The term epigenetics refers to cellular mechanisms that affect gene expression without changing DNA sequence (36). Epigenetic markings can be inherited and modified throughout the lifespan (37). Epigenetic modifications during critical early periods, such as embryogenesis (38) have the most effect on phenotype. Fetal and early life exposures have been associated with numerous health outcomes later in life, including obesity (39,40). Changes to DNA marking and packaging may explain the influence of the environment on gene expression throughout a person’s life and even across generations (41). Evidence is mounting from experimental studies in animals and from human epidemiologic studies that epigenetic mechanisms may affect risk for chronic disease, especially when the environment predicted by fetal experience does not match the environment later in life (42,43).

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Preventing Chronic Disease: July 2009: 09_0011