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103. Alhazzani W, Jacobi J, Sindi A, et al. The effect of selenium therapy on mortality in patients with

sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care

Med 2013;41:1555–1564.

104. Abel RM, Beck CH Jr, Abbott WM, et al. Improved survival from acute renal failure after treatment

with intravenous essential L-amino acids and glucose. Results of a prospective, double-blind study.

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105. Bal BS, Finelli FC, Shope TR, et al. Nutritional deficiencies after bariatric surgery. Nat Rev

Endocrinol 2012;8:544–556.

106. Gletsu-Miller N, Wright BN. Mineral malnutrition following bariatric surgery. Adv Nutr 2013;4:506–

517.

107. Isom KA, Andromalos L, Ariagno M, et al. Nutrition and metabolic support recommendations for

the bariatric patient. Nutr Clin Pract 2014;29(6):718–739.

108. Kaafarani HM, Shikora SA. Nutritional support of the obese and critically ill obese patient. Surg Clin

North Am 2011;91:837–855, viii–ix.

109. Morley JE. Anorexia of aging: a true geriatric syndrome. J Nutr Health Aging 2012;16:422–425.

110. Morley JE. Pathophysiology of the anorexia of aging. Curr Opin Clin Nutr Metab Care 2013;16:27–

32.

111. Wilmore DW. The effect of glutamine supplementation in patients following elective surgery and

accidental injury. J Nutr 2001;131:2543S–2549S; discussion 2550S–2551S.

112. Alexander JW, MacMillan BG, Stinnett JD, et al. Beneficial effects of aggressive protein feeding in

severely burned children. Ann Surg 1980;192:505–517.

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Chapter 4

Obesity and Metabolic Disease

Robert W. O’Rourke and Michael W. Mulholland

Key Points

1 Obesity is a polygenic phenomenon, and up to 70% of the propensity to a specific body habitus is

due to genetic influences.

2 Epigenetics and environment interact with genetics to produce the obesity phenotype.

3 The hypothalamic feeding center is a dominant central site of control of energy homeostasis and

receives multiple afferent inputs and delivers diverse efferent outputs to all organ systems.

4 Control of food intake via satiety and hunger is a dominant mechanism of regulation of body weight,

but other processes contribute, including but not limited to metabolic rate, adipocyte physiology,

and the microbiome; alterations in the set-points and regulation of these processes have been linked

to the development of obesity.

5 Nutrient excess is a key early trigger in the development of cell stress that underlies the

pathogenesis of metabolic disease.

6 Adipose tissue acts as a critical nutrient “buffer” to protect other tissues from nutrient excess; as

adipose buffering capacity is overwhelmed, nutrient excess overflows to all tissues, inducing

metabolic disease.

7 Hepatic steatosis and peripheral and central insulin resistance are dominant features of metabolic

disease, but metabolic disease encompasses all organ systems with pleiotropic pathology.

GENETICS OF OBESITY

Metabolic thrift: Obesity is encoded within the human genome. The thrifty gene hypothesis, proposed by

geneticist James Neel, posits that humans are predisposed to a thrifty metabolism by genes selected over

eons of evolution in environments characterized by food scarcity.1 These genes were adaptive in our

ancient past but in our modern environment lead to a blossoming of obesity. In the past 50 years, the

very genes which drive us to seek out calorie-dense food have led us to create, for the first time in

human history, an obesogenic environment in which food is plentiful. While competing theories exist,

such as predation release and genetic drift, Neel’s thrifty gene hypothesis remains the basis of a modern

understanding of obesity as a genetic phenomenon.

Metabolic thrift is a feature of all life, which exists in a perpetual struggle for energy resources.

Strategies of metabolic thrift include high caloric intake, body temperature regulation, torpor, and

hibernation. Humans practice thrift by storing energy in the form of adipose tissue. Lipid is not only

energy dense, but also water insoluble, and thus can be stored in large quantities in cells without

disrupting osmotic gradients. Because of these unique characteristics, virtually all life-forms use lipid as

an energy storage molecule. Lipid droplets are found in yeast, Drosophila stores lipid in a specialized

“fat body,” and migratory geese store lipid in hepatocytes. Humans, along with many other vertebrates,

store large amounts of lipid in adipose tissue, which can provide energy for months; monitored fasts of

over a year have been documented in obese humans.2 Adipose tissue accumulation is not the only

mechanism of human metabolic thrift. Insulin resistance is thought to have evolved in humans to

protect against hypoglycemia during periods of fasting and famine. The carnivore hypothesis posits that

insulin resistance appeared in primates with the onset of the ice age when food became scarce and

primates shifted away from a carbohydrate-rich diet toward a protein-rich diet, an evolutionary heritage

that explains the link between obesity and diabetes.

1 Modern genetics and human obesity: Compelling data support the contention that obesity is rooted in

genetics. Quantitative analysis of twin studies, in which phenotypic traits of thousands of twin pairs are

analyzed using statistical methods based on Mendelian principles, is a well-accepted method for

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quantifying the contribution of genetics to a given phenotype or disease. Multiple twin studies have

consistently demonstrated that approximately 70% of the tendency toward obesity is due to genetics,

with the remainder presumably due to environmental influences.3 Genome-wide association studies extend

these data and permit study of human genetics at the nucleotide level. These studies involve sequencing

the genomes of thousands of patients and correlating single-nucleotide polymorphisms (SNPs) with

phenotypic traits and disease states. Association studies have begun to identify the thrifty genes that

Neel postulated decades earlier. Many SNPs that correlate with obesity lie within genes that are directly

associated with body weight regulation. Others lie in genes that are not as clearly related to energy

balance, including genes that regulate neural and limb development, DNA repair, and many other

cellular functions, testament to the fact that the processes that regulate energy homeostasis overlap

with all aspects of physiology. As SNP data emerge, it has become clear that the effect size of each

individual SNP’s contribution to the obesity phenotype is small, on the order of <1% to 3%, and that

potentially hundreds of SNPs contribute to obesity. Obesity, like many chronic diseases, is a complex

polygenic phenomenon. Genetic studies have so far identified over 50 SNPs that correlate with human

obesity, and the list continues to grow.4

2 Epigenetic mechanisms contribute to obesity. The thrifty phenotype hypothesis was proposed by Hales

and Barker in 1992 to explain the observation that infants born to malnourished mothers are at

increased risk of adult obesity and metabolic disease compared to offspring born of the same mothers

during well-nourished pregnancies.5 The fetus was presumed to be responding to instability in

environmental food resources by adjusting its phenotype toward a thrifty metabolism, a phenomenon

termed fetal programming. A similar response was subsequently observed in fetuses born of obese and

diabetic mothers.6 Excess or scarcity of nutrients may be interpreted similarly by the fetus as signs of

unstable food resources, which may explain the similar effect of maternal under- and overnutrition on

offspring metabolic phenotype. Subsequent research has demonstrated that these effects are mediated

by epigenetic mechanisms which involve covalent modification of DNA independent of changes in

Watson–Crick base-pair sequence, including DNA methylation and glycosylation and histone

modification. These changes may persist for one or more generations. Research over the past two

decades has revealed that epigenetic modification of the genome is widespread, occurs primarily during

fetal development but may extend into adulthood, and regulates normal developmental and homeostatic

processes as well as pathologic responses. Epigenetics allows the fetus to respond in utero to

environmental cues delivered by changes in maternal homeostasis, the so-called “weather forecast”

model.7 Epigenetic modifications in response to fetal under- and overnutrition have been demonstrated

in animals and humans, play an important role in disease pathogenesis, and speak to the fact that

intervention must occur early, prior to birth, to prevent adult obesity and metabolic disease. The

metabolic dice are cast in utero.

Human metabolic diversity and the role of environment: The multiple thrifty SNPs in the human genome

impart marked genetic heterogeneity that underlies the intrinsic variability of the human body habitus,

with a wide range of body types from lean to obese. This heterogeneity extends to all aspect of

metabolism, with individual differences in satiety and hunger thresholds, metabolic rates, metabolic

handling of lipid and glucose, variability in adipocyte proliferation and hypertrophy capacities, and

differing propensities to insulin resistance and hyperlipidemia. This heterogeneity explains the diversity

of the obesity phenotype with its different sites of accumulation, including visceral and subcutaneous,

and its variable ages of onset, triggers, severity, and responses to diet- and surgery-induced weight loss.

The human species is highly metabolically diverse, a trait that had been critical to our success, allowing

us to adapt to a wide range of habitats as we colonized the globe. Multiple examples exist of human

subpopulations whose genetic heritages are adaptive in their native environments, but maladaptive in a

modern obesogenic environment. Polynesians provide an example of a human subpopulation with a

marked genetic propensity to obesity and insulin resistance, traits that provided a selective advantage in

the ancient South Pacific environment, which was characterized by labile food supplies and transoceanic

voyages that entailed a high risk of starvation. This genetic heritage, in our modern environment, places

Polynesians at exceptionally high risk for obesity and metabolic disease. Similar human subpopulations

metabolically adapted to specific niche environments but at high risk for metabolic disease in

industrialized society include Inuit Eskimos, Aboriginal Australians, and Pima Indians (Fig. 4-1).

Environment plays a critical role in the pathogenesis of obesity. Dominant modern environmental

contributors are an excess of processed food and a structured built environment that discourages physical

activity. Modern processed food is not only calorie dense but also highly palatable, and stimulates

central nervous system (CNS) reward centers and hunger/satiety circuits not designed for chronic

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stimulation, thus reinforcing overeating. Physical activity is markedly decreased in our modern

environment relative to our distant past. Paleolithic humans were estimated to have consumed 30%

more calories than modern humans but engaged in significantly higher levels of physical activity.8

Other factors also contribute to a lesser extent, including disruption in Circadian rhythms, stability in

home temperatures, and assortative mating patterns. An evolving field of environmental engineering

has arisen to address these issues.

Figure 4-1. Interactions between environment and genetics dictate phenotype. A: Environment alters genetics over millennia,

while the effects of environment on epigenetics take place over generations. In the case of humans, genetics dictates our behavior

which in turn has led us to create an obesogenic environment, creating a vicious cycle that exacerbates the obesity epidemic. B:

The obesity phenotype blossoms in a modern obesogenic environment, with the population body mass index (BMI) curve

broadening and shifting rightward, with an increase in median BMI. The increase in median BMI is relatively modest, but a

substantially larger percentage of people populate overweight and obese BMI ranges. Of note, the schematic graphs shown are

similar to those that describe the shift in US population BMI National Health and Nutrition Examination Survey data from the late

1970s to the early 2000s.

PHYSIOLOGY OF OBESITY

3 The adipostat: A dominant determinant of systemic metabolic homeostasis is the quantity of existent

adipose tissue stores, the adequacy of which is determined by the hypothalamic feeding center (HFC).

The HFC receives multiple afferent neural and hormonal inputs from all organ systems, including

adipose tissue, and orchestrates a range of responses via efferent outputs that regulate all aspects of

metabolism. These multiple HFC-regulated systems monitor and maintain adipose tissue stores, and

together comprise the adipostat, the sum total of all processes that defend body weight. The amount of

adipose tissue deemed adequate by the HFC varies among individuals and is dictated by multiple poorly

understood thrifty genes. Collectively, these genes and the proteins they regulate define the adipostat

set-point, which determines the degree of metabolic thrift of an individual. The hypothalamus of a lean

person “considers” a lower amount of adipose tissue to be adequate, while the hypothalamus of an

obese person requires higher levels of baseline adipose tissue stores. Weight loss alerts the HFC to

deviation from the adipostat set-point and triggers robust compensatory metabolic responses that act to

restore adipose tissue mass to baseline levels, including but not limited to increased hunger, decreased

satiety, and decreased metabolic rate. The HFC resides deep in the midbrain, far removed from the

frontal cortex, the seat of conscious thought and what we refer to as “willpower.” HFC-mediated

metabolic responses are characterized by tight regulation; deviation outside the range of these responses

for more than limited periods of time is not possible based on conscious choice, explaining the nearuniversal failure of conscious dietary efforts to lose weight. Obese patients are able to control their

weight only to a point, and only for brief periods, after which compensatory responses are activated.

These mechanisms also explain the lack of efficacy of liposuction as a tool for weight loss. Regardless of

the method, whether diet-induced or liposuction, reduction in adipose tissue mass activates

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induced weight loss is the only exception to this rule, inducing poorly understood paradoxical responses

that bypass the adipostat, including decreased satiety and increased metabolic rate.

Multiple physiologic mechanisms comprise the adipostat and regulate body weight. Most important in

humans are the collective satiety and hunger systems that regulate food intake. Less powerful but

nonetheless important are mechanisms that control metabolic rate, adipocyte physiology, and the

microbiome.

4 Satiety and hunger: Regulation of food intake is the dominant mechanism by which humans control

body weight. This is not true for all species. While food intake is an important mechanism of energy

homeostasis in mice, regulation of metabolic rate plays a greater role in mice than in humans. Food

intake in humans is controlled by a family of proteins that regulate satiety and hunger primarily by

acting on receptors within the hypothalamus. These diverse proteins are secreted by multiple organ

systems, including but not limited to adipose tissue, the gut, the liver, and the skeletal muscle.

The Ob mouse, a genetic mutant strain described in 1950, manifests an obese phenotype, along with a

range of other abnormalities related to immune, endocrine, and reproductive functions. The Ob mouse

harbors an inactivating point mutation in the leptin gene (Gr. leptos, thin). Leptin is a 16-kD satiety

hormone secreted by adipose tissue in response to a meal that in turn acts on receptors within the HFC

to induce satiety. Leptin establishes communication between adipose tissue, the gut, and the brain that

signals the status of adipose tissue stores to the brain, which in turn dictates food intake. As such, leptin

represents a paradigmatic mediator of the adipostat, and an example of the complex interorgan

communication that underlies its function (Fig. 4-2). Soon after the cloning of the leptin gene in 1994,9

rare humans with leptin mutations were identified with an Ob phenotype that was reversed with

administration of exogenous recombinant leptin. Unfortunately, similar therapy was ineffective in

common human obesity, which is not due to a single-leptin mutation, but rather is polygenic and

characterized by hypothalamic resistance to leptin satiety effects. Nonetheless, the discovery of leptin

led to an explosion of satiety and hunger research, and over the ensuing decade multiple satiety and

hunger proteins were described.

Figure 4-2. Leptin mediates communication between adipose tissue, gut, and brain. A: Signals from the gastrointestinal tract

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