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overwhelmed, inducing cell stress responses in all tissues that underlie the pathogenesis of metabolic

disease (Fig. 4-7).

Figure 4-7. Adipose tissue overflow, interorgan communication, and systemic metabolic disease. As adipose tissue buffering

capacity is overwhelmed, lipids, nutrients, cytokines, and adipokines overflow into the systemic circulation and cause systemic

metabolic disease via the same cellular effects that initially unfold in adipocytes. Early overflow occurs via the portal system,

which drains visceral adipose tissue venous effluent into the liver, which becomes the first site of systemic metabolic disease and

an important secondary site of nutrient buffering via the development of hepatic steatosis. Overflow progresses to involve all

peripheral tissues, inducing cell stress and disease in all organ systems. Overflow involves the central nervous system as well, as

inflammation and cell stress have been documented in the hypothalamus in obesity, which in turn is thought to disturb peripheral

metabolic function via alterations in CNS efferent signaling.

Nutrients and metabolites are central mediators of the systemic effects of adipose tissue overflow.

Free fatty acids mediate systemic lipotoxicity, a central mechanism of metabolic disease. Free fatty acids

trigger inflammation via binding to Toll-like receptors, and also act as ligands for multiple other

immunostimulatory and cell stress-inducing receptor families. Lipid metabolites induce cellular insulin

resistance, ER stress, and apoptosis. Metabolic products of glucose and fructose, including advanced

glycation end products and glucosamines, mediate similar effects. Cytokines and adipokines overflow

from adipose tissue as well. TNF-α, a dominant inflammatory cytokine expressed by ATM in obesity,

exerts proinflammatory and diabetogenic effects on tissues via diverse mechanisms. Leptin also

promotes inflammation and regulates cellular glucose homeostasis. Expression of adiponectin, which

attenuates inflammation and has beneficial effects of cellular metabolism, is decreased in obesity, as

adipose tissue’s cytokine and adipokine balance shifts toward a proinflammatory milieu. Metabolites,

adipokines, and cytokines establish in multiple tissues the same cellular stress responses that initially

unfold in adipose tissue, including ER stress, oxidative stress, and inflammation. Within target tissues,

as in adipose tissue, these processes potentiate one another and exacerbate cell stress, forming the basis

for systemic metabolic disease.

7 Portal overflow and liver disease: The liver is one of the first organs to be affected by failure of

adipose tissue buffering, as portal overflow induces hepatic steatosis. Hepatic steatosis is the result of an

imbalance in the delivery and export of hepatocyte lipid. Sources of hepatic lipid include fats absorbed

from the diet and delivered from the gut as chylomicrons, lipids synthesized by hepatocytes via de novo

lipogenesis, and free fatty acids delivered from VAT via the portal venous system and from

subcutaneous adipose tissue via the systemic venous system. Free fatty acids from adipose tissue are a

dominant source of hepatic lipid in obesity, constituting over 60% of lipid delivery to the liver.24 Lipids

are exported from the liver primarily in the form of very low-density lipoproteins (VLDL).

Abnormalities in each of these aspects of hepatic lipid delivery and efflux that contribute to steatosis

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have been identified in obese animals and humans, including increased free fatty acid delivery to the

liver from increased adipose tissue stores, increased hepatocyte de novo lipogenesis, and decreased

VLDL secretion.

As lipid storage capacity is reached, hepatocytes experience ER stress, oxidative stress, and

inflammatory responses via similar mechanisms as in adipose tissue, causing steatohepatitis, a histologic

entity characterized by Mallory bodies, hepatocyte ballooning, and an inflammatory infiltrate consisting

of macrophages (Kupffer cells) and other leukocytes. As in adipose tissue, TNF-α plays a central role in

the hepatic inflammatory state, and neutralization of TNF-α ameliorates steatohepatitis in mice and is

under study as therapy in humans with promising results.25,26 IL-6 and other inflammatory cytokines

have also been implicated as mediators of steatohepatitis.

Steatosis is strongly associated with obesity and is present in over 90% of patients with a BMI >40.

Up to 30% of these patients will develop steatohepatitis and 10% to 30% of patients with steatohepatitis

will develop cirrhosis. Genetics contributes to these risks: ethnic predispositions to steatosis and

steatohepatitis exist, with Asians and Hispanics at higher risk than Caucasians or Blacks. Weight loss

secondary to diet or bariatric surgery reverses steatosis and halts progression of steatohepatitis in most

patients. Few pharmacologic options exist that specifically treat obesity-associated liver disease.

Diabetes: Insulin resistance is a central metabolic response of all cells to stress. ER stress, oxidative

stress, and inflammation each induce insulin resistance. Insulin resistance begins in adipose tissue. Free

fatty acids are central mediators of cellular insulin resistance. Insulin regulates not only glucose

homeostasis in adipocytes, but also lipid metabolism, inhibiting lipolysis and free fatty acid release.

Early nutrient excess, with resultant ER stress and oxidative stress, induces insulin resistance in

adipocytes, not only impairing adipocyte glucose uptake, but also attenuating insulin’s inhibitory effects

on lipolysis and thus increasing free fatty acid release by adipocytes. Free fatty acids in turn trigger

inflammation via activation of Toll-like receptors on resident adipose tissue inflammatory cells,

inducing expression of inflammatory cytokines, including TNF-α. TNF-α plays a central role in the

evolution of insulin resistance, regulating the expression and phosphorylation of multiple genes

involved in glucose homeostasis, including insulin receptor, insulin receptor substrates, the cell

signaling nexus protein Akt, and glucose transporter molecules. TNF-α also promotes lipolysis, further

exacerbating insulin resistance and free fatty acid release by adipocytes. While multiple other mediators

contribute, these interactions between free fatty acids and TNF provide a cogent example of the vicious

cycle established in adipose tissue that contributes to worsening insulin resistance.

As adipose tissue lipid buffering capacity is overwhelmed, free fatty acids overflow into the systemic

circulation, resulting in lipotoxicity, which underlies the pathogenesis of insulin resistance in all

peripheral tissues. Skeletal muscle, responsible for 60% to 80% of systemic glucose disposal, is a

dominant site of systemic insulin resistance. Similar to adipocytes and hepatocytes, skeletal muscle

myocytes accumulate lipid and exhibit ER stress, oxidative stress, and inflammation which contribute to

insulin resistance via mechanisms described above. Skeletal muscle, like adipose tissue, becomes

inflamed, with increased levels of macrophages and diabetogenic inflammatory cytokines. Increased

circulating free fatty acids also have important metabolic effects on the liver and skeletal muscle. As

lipid delivery to skeletal muscle and liver increases, energy production shifts from glucose utilization to

fatty acid oxidation. Increased free fatty acid beta-oxidation is associated with increased

gluconeogenesis in the liver and a reduction in glucose utilization in skeletal muscle, exacerbating

hyperglycemia. The initial response of pancreatic beta cells to the resultant peripheral insulin resistance

is a compensatory increase in insulin secretion, leading to hyperinsulinemia. As disease progresses,

lipotoxicity and cell stress responses affect pancreatic beta cells. Beta cell exhaustion ensues, insulin

secretion decreases, and insulin resistance progresses to frank diabetes.

Type 2 diabetes is strongly associated with obesity, with risk ratios increasing dramatically with

increasing BMI. Like obesity itself, genetics plays an important role: Asian, Black, and Hispanic

ethnicities are associated with increased risk and multiple SNPs that correlate with diabetes have been

identified. The specific mechanisms by which genetics contribute to increased susceptibility to cellular

insulin resistance and lipotoxicity are not yet well understood. Worldwide incidence is rapidly

increasing and diabetes represents a dominant emerging health crisis.

The obesity–cancer connection: Obesity is a strong risk factor for cancer. The incidences of almost all

types of cancer increase in a dose-dependent manner with increasing BMI, and at elevated BMI >40,

risk ratios range from 2 to greater than 6 depending on the type of cancer.27 The mechanisms

underlying the association between obesity and cancer are not well defined. At the cellular level, energy

homeostasis involves fundamental processes central to carcinogenesis, and signaling pathways activated

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by chronic overnutrition promote cell proliferation. Suggesting the potential for cancer therapy based

on manipulation of metabolism, epidemiologic data suggest that long-term metformin use is associated

with decreased cancer incidence. Chronic inflammation, characteristic of obesity and a well-established

risk factor for cancer, activates NFκB and other signaling pathways that potentiate cell proliferation,

increase production of reactive oxygen species that may contribute to oncogenic mutation, and induce

expression of inflammatory cytokines that act as cell mitogens. Overnutrition in obesity predisposes to a

state of chronic anabolism and is associated with increased expression of multiple growth factors that

may promote cancer, including insulin, insulin-like growth factor-1, and leptin. Chronic inflammation on

a background of chronic anabolism creates an ideal milieu for carcinogenesis. Steroids represent another

putative molecular link between obesity and cancer. Steroid metabolism is aberrant in obesity and

adipose tissue is a source of estrogen which may promote estrogen-responsive cancers. Finally,

adipocytes have been implicated in carcinogenesis, with data demonstrating that peritumor adipose

tissue contributes to tumor progression. In addition, adipocyte precursors home from adipose tissue

depots to tumors and provide growth factors and metabolic energy substrates that promote tumor

growth. The mechanisms by which obesity causes cancer are multiple, and as details are elucidated,

metabolism-based therapy for cancer will emerge.

CONCLUSION

Obesity is associated with an increased risk of cardiovascular disease, including hypertension,

atherosclerosis, and hyperlipidemia, the result of cell stress responses that afflict vascular tissue.

Immune diseases including allergy, atopy, and autoimmune diseases, are increased in the obese, due in

part to the above described alterations in immune and inflammatory functions. While mechanical stress

due to excess weight is a contributing factor to sleep apnea, osteoarthritis, and gastroesophageal reflux

disease, fundamental cell stress mechanisms also contribute, as inflammation has been implicated in

these diseases as well. The pan-systemic nature of metabolic disease provides substantial opportunity for

developing therapy that will simultaneously treat multiple obesity-related pathologies.

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