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Figure 4-3. A simplified schematic of the hypothalamic feeding center and its primary afferent signals. A. Multiple hormones

secreted by the gastrointestinal tract and adipose tissue act as afferent signals that impact on the arcuate nucleus (ArcN) within the

hypothalamic feeding center to regulate feeding behavior. B. Peripheral afferent signals impact on first-order ArcN neurons, which

in turn communicate with second-order paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) neurons to coordinate

behavioral and metabolic output. PVN signaling is primarily anorexigenic and catabolic, and is enhanced by leptin and insulin,

while LHA signaling is primarily orexigenic and anabolic and inhibited by leptin and insulin. Higher-order anorexigenic PVN

outputs include corticotropin-releasing hormone (CRH), oxytocin, and thyrotropin-releasing hormone (TRH); higher-order

orexigenic LHA outputs include melanin-concentrating hormone (MCH) and orexins A and B. Both pathways negatively regulate

the other. Other peripheral and central mediators stimulate first- and second-order neurons as well, including ghrelin, CCK, GLP-1,

serotonin, endogenous cannabinoids, and norepinephrine.

Adipocyte physiology: Adipocytes arise from mesenchyme-derived adipocyte stem cells within adipose

tissue. Nomenclature is evolving and includes the terms preadipocyte or adipocyte/adipose tissue stem cell.

Adipocyte stem cells are pluripotent, and depending on the stage of differentiation, may give rise to

adipocytes, fibroblast, myocytes, and other cell types. Multiple adipocyte stem cell subpopulations give

rise to adipocytes of variable phenotypes, including white, brown, and beige. Evidence suggests that

hematopoietic precursor cells may also give rise to adipocytes.

Until recently it was thought that adipocyte stem cell proliferation, that is, hyperplasia, did not occur

in postnatal humans, and that adipocyte hypertrophy was the primary mechanism of increased adipose

tissue mass in obesity. Recent data suggest that both hyperplasia and hypertrophy contribute to

evolving obesity, with hyperplasia predominating during childhood and hypertrophy predominating

during adulthood. These data derive in part from ingenious methods studying incorporation of C14 into

adipocyte DNA in individuals born before and after mid-20th century nuclear bomb testing, which raised

environmental C14 levels.12 Data over the last decade have demonstrated that adipocyte hyperplasia

and proliferation are highly regulated and that aberrations in these processes contribute to obesity.

Adipocyte necrosis and apoptosis as a result of hypoxia and nutrient excess (described below) are

matched by increased adipocyte stem cell proliferation and differentiation. Furthermore, adipocytes

from obese humans demonstrate increased hyperplastic and hypertrophic capacities, contributing to

increased adipose tissue mass with progressive obesity.13 The epigenetic programming of adipocyte

stem cells during fetal development may underlie some of these differences in adipocyte behavior

observed between obese and lean subjects. Defining regulatory mechanisms of adipocyte growth is an

active area of research and will lead to methods to manipulate adipocyte biology and treat obesity at its

source.

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Figure 4-4. Primary peptide mediators of energy homeostasis. Cytokines, adipokines, and gut peptides regulate diverse aspects of

metabolism to control global energy homeostasis. Each of these proteins has dominant functions within its primary family, but also

demonstrates cross-regulatory functions in other domains. In addition, mediators participate in crosstalk at the level of cellular

receptors and downstream intracellular signaling mediators. Shown are only partial lists of peptides and the physiologic functions

they control.

The microbiome: In a very real sense, the microbiome may be considered a distinct organ system much

like cardiopulmonary, gastrointestinal, or renal systems, and like any organ system, aberrations in the

microbiome contribute to the pathophysiology of disease. The microbiome plays an important role in

energy homeostasis. Animals raised in germ-free environments manifest increased food intake but

decreased body weight and do not develop obesity and insulin resistance when fed a high-fat diet,

demonstrating that gut microbiota contribute to nutrient digestion. Gut microbiota ferment nonhostdigestible polysaccharides into absorbable monosaccharides and short-chain fatty acids that are absorbed

by host enterocytes and colonocytes. Products of microbiota fermentation act not only as nutrients, but

also regulate host metabolism: short-chain fatty acids induce host satiety, mediated in part by increased

secretion of GLP-1 and peptide YY and decreased secretion of ghrelin. Separate data demonstrate

interactions between microbiota and adipose tissue, liver, skeletal muscle, and CNS. These effects are

mediated by short-chain fatty acids, activation of Toll-like receptors on host cells via lipopolysaccharide

and other bacterial products, regulation of host systemic and cellular metabolism, and other diverse

mechanisms, all of which affect diverse aspects of host energy homeostasis.

Alterations in microbiome–host interactions contribute to the pathogenesis of obesity and metabolic

disease. Germ-free mice, when colonized with stool from obese mice, gain more weight than mice

colonized with stool from lean mice, demonstrating an obesity-specific microbiome. The ratio of gut

Firmicutes/Bacteroidetes species is increased in obese mice and humans. Ongoing research has begun to

identify specific subspecies within these broad categories of bacteria that are altered in obesity and

metabolic disease to provide a higher-resolution picture of the microbiome in obesity. For example,

obesity in mice and humans is associated with an increase in gram-negative gut bacteria, with a

concomitant increase in lipopolysaccharide absorption from the gut, which has been postulated to

contribute to obesity-associated inflammation and insulin resistance. The tools used to evaluate the

microbiome are rapidly evolving. Sequencing of the microbial genome using ribosomal 16S is well

established, while evolving technologies include shotgun sequencing of the entire metagenome and

functional assays involving transfer of human microbiota in the form of stool into germ-free animals to

study in vivo effects. Manipulation of the microbiome holds significant promise. Prebiotic

(nondigestible bacterial nutrients) and probiotic (specific bacterial subspecies thought to confer systemic

benefits) therapies are areas of active research, while antibiotic therapy directed against gram-negative

bacteria reduces steatosis and systemic inflammation in obese rodents.

Summary: Satiety and hunger, metabolic rate, adipocyte physiology, and the microbiome are but a

few of the many processes that regulate metabolism and are dysregulated in obesity. Differences in lipid

and glucose metabolism, immune function, central and peripheral nervous system function, and multiple

other processes that impact upon energy metabolism contribute to the wide variability of the obesity

phenotype in humans. This variability is the result of genetic polymorphisms that contribute to

metabolic diversity among humans and the wide range in human body habitus. The question is often

posed as to whether obesity should be considered a disease. Rather, obesity is better thought of as a

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maladaptive compensatory response to an environment that is radically different than that in which our

species evolved. The obesity phenotype remained relatively underexpressed in environments of food

scarcity in which we evolved, in which obesogenic genes acted to defend adipose tissue stores and

enhance survival, but blossoms in our modern environment. An understanding of this intimate interplay

between phenotype and environment will lead to novel therapy for obesity based on manipulation of

environment and genetics.

PATHOPHYSIOLOGY OF METABOLIC DISEASE

Obesity and metabolic disease: Obesity is associated with a range of pathology involving every organ

system collectively referred to as metabolic disease. While underlying mechanisms are multiple, the

root cause of all metabolic disease is a failure of adipose tissue nutrient buffering capacity, leading to

overflow of nutrients, metabolites, cytokines, and adipokines from adipose tissue to other tissues. The

clinical effects of overflow differ depending on the target tissue, but the fundamental cellular responses

to nutrient excess common to all tissues, adipose included, involve mechanisms by which cells control

nutrient flux and respond to nutrient excess. These cellular responses underlie the pathophysiology of

metabolic disease.

5 Metabolism, nutrient excess, and the root cause of metabolic disease: Energy homeostasis is the

dominant and overriding goal of all biologic systems. Metabolism (Gr. metabole, change) may be

defined as the sum total of all chemical reactions and physiologic processes that regulate cellular and

systemic energy homeostasis. At the cellular level, metabolic processes are fundamental to all metazoan

life and are highly conserved across phyla; examples include the citric acid cycle and mitochondrial

respiration, which utilize multiple enzymes, the structure and function of which are conserved from

yeast to humans. At the systemic level, metabolic processes are central to maintaining homeostasis and

interface with virtually with every organ system and every physiologic process. The basic substrates of

metabolism are the macro- and micronutrients that comprise the stuff of cells and tissues, the fatty

acids, amino acids, and carbohydrates and their derivatives that are the constituents of complex

macromolecules, and the micronutrients that contribute to the catalysis of reactions that synthesize and

degrade macronutrients and higher-order macromolecules. In one sense, all cells are simply

clearinghouses for nutrients. Cellular nutrient flux provides substrate for synthesis of macromolecules

via anabolic metabolic processes, which are in turn degraded via catabolic metabolic processes.

Maintaining the balance between anabolism and catabolism at cellular and systemic levels is of critical

importance. Cancer, for example, may be viewed as a metabolic imbalance that favors cellular

anabolism over catabolism. Cachexia, in contrast, may be considered as a metabolic disorder that favors

systemic catabolism over anabolism.

The nutrient flux with which cells are constantly faced determines the balance between anabolism and

catabolism and dictates organism-wide energy homeostasis. Nutrients are, by their very nature, highenergy capacity molecules, much like oxygen, and like oxygen, are capable of participating in energyintensive and potentially damaging reactions. Fatty acid metabolites such as ceramides and

diacylglycerols, and glucose metabolites including advanced glycation end products and glucosamines,

trigger inflammation, oxidative stress, and insulin resistance at the cellular level.

Excess nutrients are therefore potentially damaging to cells, and cellular physiology has evolved

processes designed to control exposure, flux, and sequestering of these high-energy molecules. These

cellular processes were selected by evolution to manage transient nutrient excess, but are not well

adapted to manage chronic nutrient excess, a situation that cells only rarely encountered during

evolution. Maladaptive cellular responses to chronic nutrient excess underlie the pathogenesis of all

obesity-related disease and occur in all cells, explaining the involvement of virtually every organ system

in metabolic disease. These processes consist of a triumvirate of fundamental cellular stress responses:

endoplasmic reticulum (ER) stress, oxidative stress, and inflammation.

Cellular responses to excess nutrient flux: The ER is a complex organelle present in virtually all

eukaryotic cells that orchestrates synthesis, folding, and intracellular transport of macromolecules. The

rough ER, studded with ribosomes, is predominantly responsible for protein synthesis, while the smooth

ER is predominantly responsible for lipid and carbohydrate synthesis. The ER receives a constant influx

of nutrient substrates, which it sequesters and directs toward macromolecule synthesis or degradation,

thus carefully metering cellular nutrient exposure. In this capacity, the ER acts as a nutrient sensor,

responding to changes in cellular nutrient flux by directing cellular anabolism and catabolism

accordingly. The ER also responds to other cell stressors, including hypoxia, toxins, disturbances in

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electrolyte or micronutrient balance, and a host of other stimuli that alter cell homeostasis. Excess

cellular nutrient flux, like other forms of stress, leads to a series of stepwise ER responses that are

collectively referred to as the ER stress response.

The initial ER stress response to modest increases in nutrient flux involves increased expression of

chaperone proteins involved in macromolecule synthesis to accommodate increased anabolism of excess

nutrients. If nutrient excess persists to exceed the capacity of cellular macromolecule synthesis and

nutrient sequestration, the ER stress response progresses to activate the unfolded protein response. The

unfolded protein response downregulates global protein expression while upregulating expression of

chaperone proteins in an adaptive response designed to maintain synthesis of essential cellular proteins.

If nutrient excess persists beyond the capacity of the ER to maintain proper protein synthesis, then the

unfolded protein response progresses to induce cell apoptosis. The unfolded protein response thus

protects cells from modest increases in nutrient flux and induces cell death in the face of extreme

nutrient excess.

The ER stress response is not the only cellular response to nutrient excess. Macromolecule synthesis

generates reactive oxygen species (e.g., superoxides, oxygen/hydroxyl-free radicals, hydrogen peroxide)

which, like nutrients, are highly energetic molecules capable of damaging cells. Cells have evolved

multiple mechanisms to sequester reactive oxygen species and manage oxidative stress, including

antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, scavenging

molecules such as ascorbic acid, urate, and divalent ions, and the thioredoxin and glutaredoxin systems.

The ER and mitochondria are primary cellular sites of control of oxidative stress. When nutrient flux,

macromolecule synthesis, and reactive oxygen species production exceed cellular antioxidant capacity,

cells activate diverse oxidative stress responses, which increase expression of antioxidant proteins,

sequester reactive oxygen species, and increase mitochondrial uncoupling, which transiently reduces

cellular reactive oxygen species production. Oxidative stress responses overlap with ER stress responses,

and if oxidative stress persists, the unfolded protein response is activated and leads to apoptosis.

The third arm of the cellular stress response is inflammation. Increased nutrient flux generates an

inflammatory response designed to scavenge debris and byproducts from increased cell turnover and

macromolecule synthesis that result from ER and oxidative stress responses. Testament to the close

relationship between metabolism and inflammation, central inflammatory and metabolic mediators

demonstrate marked functional overlap. For example, TNF-α and leptin, in addition to their dominant

functions in regulating inflammation and satiety respectively, each plays important reciprocal roles in

regulating body weight and inflammation.14,15 TNF-α and leptin are but two examples of many satiety

and hunger factors and inflammatory cytokines that manifest dual immunoregulatory and energy

homeostasis functions. In addition, molecular byproducts of metabolism trigger inflammation. Free fatty

acids are ligands for Toll-like receptors, while advanced glycation end products trigger receptors of

advanced glycation end-products pathways which directly activate innate immune effector cells,

establishing a direct molecular link between metabolism and inflammation. Obesity is associated with a

state of chronic systemic inflammation that plays a central role in the pathogenesis of multiple

comorbid diseases. Serum cytokine levels are increased in obese animals and humans, and adipose tissue

manifests a pan-leukocyte infiltrate, findings that directly correlate with the magnitude of obesity and

severity of metabolic disease.

Increased ER stress, oxidative stress, and inflammation have been demonstrated in obese rodents and

humans. An important aspect of cellular stress responses is that each potentiates the others via overlap

in fundamental cell signaling pathways including PI3-Akt, MAPK, AMPK, mTOR, JAK-STAT, and NFκB.

These signaling pathways are triggered by multiple stimuli that are dysregulated in obesity, including

adipokines, cytokines, growth factors, and nutrients and metabolites. Furthermore these signaling

pathways participate in robust crosstalk at multiple levels, establishing a vicious cycle that perpetuates

cell stress in the face of chronic nutrient excess (Fig. 4-5). These processes are common to all cells and

affect all tissues in late-stage obesity, explaining the diverse manifestations of systemic metabolic

disease. But where do these processes begin, and what initiates them? To answer this question, we must

explore the early events in adipose tissue in evolving overweight and obesity – it is within adipose

tissue that metabolic disease originates.

Adipocyte hypertrophy, hypoxia, inflammation, and fibrosis: Adipocytes are exquisitely well designed to

manage high levels of nutrients. One of the first responses of adipocytes to chronic elevations in

nutrient flux in early overweight and obesity is hypertrophy. Free fatty acids are absorbed by

adipocytes through pinocytosis mediated by fatty acid-binding proteins, as well as being synthesized

from glucose and glutamine via de novo lipogenesis, and stored in lipid droplets via a highly regulated

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process mediated by perilipin proteins. Virtually all cells are capable of storing lipid to some degree, but

adipocytes have an extremely high capacity for lipid storage and hypertrophy. Adipocytes are one of

only a few cell types that can enlarge to diameters greater than 100 microns, the diffusion distance of

oxygen. Adipocyte diameter in humans correlates directly with the magnitude of obesity and the

severity of metabolic disease; adipocytes in lean subjects are virtually all less than 100 microns in

diameter, while those in obese subjects are greater than 100 microns, in some cases exceeding 200

microns.16 Progressive adipocyte hypertrophy establishes a state of cellular hypoxia within adipose

tissue that has been verified in obese mice and humans. Decreased adipose tissue capillary density and

blood flow in obesity exacerbate hypoxia. This hypoxic state has broad effects on adipocyte metabolism,

inducing insulin resistance, ER stress, oxidative stress, and inflammation, and inhibiting lipogenesis.

Manipulation of hypoxic responses in adipocytes holds therapeutic promise. For example, targeting

hypoxia-inducible factor-1α, a dominant cellular hypoxia-response protein, in murine obesity

ameliorates metabolic disease.17

Hypoxia induces adipocyte apoptosis and necrosis which in turn recruits an inflammatory response

designed to scavenge dead and dying adipocytes. This inflammatory state is a dominant aspect of

adipose tissue dysfunction in obesity, and is directly linked to insulin resistance and dysregulation of

lipid metabolism at local (adipose tissue) and systemic levels. Central to adipose tissue inflammation is

a marked accumulation of adipose tissue macrophages (ATMs), the number of which directly correlates

with the degree of obesity in mice and humans. ATMs are important mediators of metabolic disease,

and are altered in phenotype, shifting from a scavenging M2 phenotype to an inflammatory

diabetogenic M1 phenotype.18 ATMs are a dominant source of inflammatory cytokines, including TNFα, IL-6, and IL-1, all of which induce insulin resistance and aberrations in glucose and lipid metabolism

in adipocytes via multiple mechanisms. In support of a central role for ATMs in the pathogenesis of

metabolic disease, mice transgenically engineered to lack macrophage homing molecules in adipose

tissue do not develop obesity-related ATM infiltrates and are protected from diabetes. Preliminary trials

of pharmacologic agents that interfere with macrophage homing to adipose tissue in humans show

promise as treatment for diabetes. Finally, adipose tissue inflammation in obesity involves more than

macrophages, and is associated with a pan-leukocyte infiltrate that includes T-cells, B-cells, NK cells,

NKT cells, and eosinophils. Therapy for metabolic disease based on nonmacrophage cellular immune

mediators is an area of active research.

Figure 4-5. Highly simplified schematic of major cell signaling pathways that regulate energy homeostasis and cell stress

responses. Primary stimuli for all cells include adipokines, insulin, IGF-1, nutrients and metabolites including free fatty acids, and

their derivatives such as ceramide (which activate Toll-like receptors, TLR), glucose, fructose, and advanced glycation end products

(which activate receptors for advanced glycation end products, RAGE), and cytokines. Primary intracellular signaling nexi include

mitogen-activated protein kinases (MAPK), PI3-Akt, JAK/STAT signaling mediators, AMP-activated protein kinase (AMPK),

mammalian target of rapamycin (mTOR), and NFκB, all of which are linked to ER stress and oxidative stress responses. These

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pathways engage in highly redundant crosstalk via cross-reactivity of intracellular signaling mediators and induction of gene

transcription, and conspire to integrate multiple stimuli to regulate fundamental aspects of cell metabolism, survival, and death in

response to nutrient availability and cell stressors such as hypoxia.

6 As inflammation persists, adipose tissue undergoes fibrotic remodeling, with increased expression of

matrix metalloproteases and collagens and increased extracellular matrix turnover. Adipose tissue

fibrosis limits adipocyte hypertrophic and lipid storage capacity, accelerating adipocyte stress. Obese

collagen VI knockout mice demonstrate increased adipocyte hypertrophic capacity due to decreased

fibrosis and are protected from systemic metabolic disease.19 These observations speak to a critically

important role for adipose tissue as a buffer for excess nutrients, metabolites, and metabolic toxins. As

obesity progresses, adipose tissue buffering capacity is overwhelmed and cell stress responses, initially

confined to adipose tissue, overflow into circulation and cause systemic metabolic disease (Fig. 4-6).

Adipose tissue anatomy, adipose tissue overflow, and the pathogenesis of systemic metabolic disease: Patients

with rare congenital and acquired lipodystrophy syndromes characterized by a paucity of adipose tissue

suffer from metabolic disease just as in obesity, including insulin resistance, hyperlipidemia, and hepatic

steatosis, demonstrating that the absence of adipose tissue is as detrimental as its excess. In

lipodystrophy and obesity, adipose tissue nutrient buffering capacity is overwhelmed, and nutrients

overflow to other tissues not as well adapted as adipose tissue to manage nutrient excess, inducing

systemic metabolic disease.

Adipocytes are present throughout the mammalian body in discrete anatomic depots as well as within

every organ and every tissue. Adipose tissue is more than simply a storage depot for lipid; only half the

cells in adipose tissue are adipocytes, the remainder comprising the so-called stromovascular cell

fraction, which consists of immune leukocytes, fibroblasts, endothelial cells, adipocyte stem cells, and

other cell types. Adipose tissue is highly innervated with sympathetic and parasympathetic afferent and

efferent fibers, and has important immunoregulatory and endocrine functions. Adipose tissue

participates in robust communication with the CNS and all peripheral organs, orchestrating responses to

alterations in nutrient availability, systemic health and metabolism, ambient temperature, and a host of

other stimuli. Adipose tissue is a central regulator of systemic energy homeostasis.

Hibernating bears accumulate large amounts of adipose tissue without developing inflammation or

other cellular stress responses, while in some humans, excess subcutaneous adipose tissue appears to

protect against metabolic disease. These examples demonstrate that adipose tissue phenotype is as

important as quantity with respect to systemic metabolic state. Adipose tissue may be broadly divided

into white and brown phenotypes. White adipose tissue comprises the majority of adipose tissue in

humans, is strongly associated with metabolic disease, increases with increasing obesity, and is a

primary storage site for lipid. Brown adipose tissue, in contrast, comprises a minority of total adipose

tissue in humans, has beneficial effects on metabolism, decreases with increasing obesity and with age,

and manifests lower lipid storage capacity. Brown adipocytes engage in higher levels of fatty acid

oxidation and thermogenesis via expression of mitochondrial UCPs. White adipose tissue derives from

mesodermal stem cells that migrate to sites of canonical depots in humans in early embryonic

development and proliferate to form defined depots in late fetal and early neonatal periods. White

adipose tissue depots include visceral and subcutaneous, which may be further subdivided into omental,

retroperitoneal, and mesenteric visceral adipose tissue (VAT) compartments, and deep and superficial

subcutaneous adipose tissue compartments, each with distinct functional characteristics. Brown adipose

tissue develops in rodents during gestation from precursor cells that also give rise to myocytes and form

defined brown adipose tissue depots prior to birth. Brown adipose tissue in humans is less well

understood; while most voluminous in the neonatal period, positron emission tomography scanning

demonstrates cervical, supraclavicular, mediastinal, paraspinous, and perirenal brown adipose tissue

depots in adult humans as well.20

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Figure 4-6. Nutrient excess and cell stress in adipocytes. Nutrient excess is an early signal that induces ER stress and hypertrophy in

adipocytes. ER stress is tightly linked to oxidative stress and inflammation, and each of these processes induces and potentiates the

others. As hypertrophy progresses, adipocyte diameter expands beyond the diffusion distance of oxygen, leading to cellular

hypoxia, which exacerbates cell stress responses, leading to adipocyte apoptosis and necrosis via the unfolded protein response and

other advanced cell stress responses. Adipocyte apoptosis and necrosis trigger recruitment of an advanced inflammatory response

designed to scavenge dead and dying adipocytes. This inflammatory response is associated with fibrotic tissue remodeling which

limits adipocyte hypertrophic and lipid buffering capacity of surviving adipocytes, leading to overflow of lipids, nutrients,

metabolites, and inflammatory products from adipose tissue into the systemic circulation.

Recent data suggest that the dichotomy between white adipose tissue and brown adipose tissue is

overly simplistic, and that adipocyte phenotype spans a spectrum. An intermediate phenotype, termed

“brite” (brown-in-white) or “beige adipocytes,” is found in white adipose tissue depots in rodents and

humans. These cells manifest brown adipocyte functions, and are induced to proliferate by cold stress

and β-adrenergic stimuli, suggesting phenotypic plasticity. An important area of research is directed

toward understanding the mechanisms that regulate adipocyte phenotype. The recently described

protein irisin is secreted by skeletal muscle in response to exercise, induces a brown phenotype in

adipocytes and improves systemic metabolism when overexpressed in mice.21 This finding underscores

the importance of interorgan communication in controlling adipose tissue biology and suggests the

potential for pharmacologic mediators to manipulate adipocyte phenotype with beneficial effects on

systemic metabolism, the so-called “browning” of adipose tissue.

Human adipose tissue accumulation is anatomically heterogeneous. Human obesity may be broadly

classified into android and gynecoid phenotypes, defined by excess VAT and subcutaneous adipose

tissue, respectively. Excess VAT is strongly associated with metabolic disease; excess subcutaneous

adipose tissue, in contrast, is less strongly associated with metabolic disease, and in some studies has

been shown to be protective, suggesting a greater lipid buffering capacity. Surgical lipectomy of VAT

but not subcutaneous adipose tissue ameliorates murine diabetes.22 In contrast to mice, similar studies

of visceral omentectomy in humans demonstrate conflicting results, likely due to more complex human

adipose tissue depot anatomy, but excess VAT as measured by waist circumference and imaging

techniques nonetheless correlates strongly with metabolic disease. The reasons for the disproportionate

effect of VAT on metabolic disease are unclear. While the abdominal location of VAT plays a role,

intrinsic differences between visceral and subcutaneous adipose tissues also exist, evidenced by

experiments in which transplantation of subcutaneous adipose tissue into a visceral location ameliorates

metabolic disease in mice.23 VAT manifests higher levels of inflammation, lipolysis, β-adrenergic

receptor expression, steroid sensitivity, insulin resistance, and adipocyte proliferation and

differentiation relative to subcutaneous adipose tissue.

SYSTEMIC METABOLIC DISEASE

Mediators of systemic metabolic disease: In addition to its distinct functional phenotype, VAT also

contributes to metabolic disease via its direct anatomic communication with the liver via the portal

venous system. Portal overflow of free fatty acids, excess nutrients and metabolites, and hormones and

cytokines from VAT to the liver is an early step in the progression to systemic metabolic disease. As it

progresses, peripheral overflow extends beyond the liver to involve all tissues. Adipose tissue overflow

affects not only skeletal muscle, vasculature, kidneys, and lungs, but also the CNS; inflammation and ER

stress have been documented in the hypothalamus in obesity, and mediate reciprocal effects on adipose

tissue and other organ systems via aberrations in CNS efferent outputs that exacerbate obesity and

metabolic disease. In essence, adipose tissue dysfunction “metastasizes” as its buffering capacity is

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