Intricacies of Fat

Introduction

It is no surprise that excess adipose tissue is unhealthful.Even before scientific data explained the pathological consequencesof excessive weight gain, it was intuitively known that beingoverweight was not healthful. The newsworthy information includesthe expansive multitude of negative effects caused by excessivefat and the elaborate mechanisms that fat uses to do its damage.

The prevailing thought for decades was that fat was a passivesite in the body for energy storage. When people eat more caloriesthan they use, the excess is stored in fat cells as triglycerides.Conversely, when the body is lacking calories in relation tothe energy expended, fatty acids are released by fat cells.

Other prevalent beliefs were that all people were born witha certain number of fat cells and that number was stable acrossthe life span. People were believed to gain weight through hypertrophyor expansion of individual cells, not through an increase inthe number of fat cells. Loss of weight was believed to occurthrough a decrease in the size of fat cells, not through a reductionin the total number of cells.¹

Over time, an entirely new understanding of fat has emerged,and what researchers were sure they understood about fat onlya few years ago was found to be incomplete or sometimes entirelywrong. Research over the past 10 years has dramatically changedthe view of fat. Fat is now classified as an endocrine organ.In fact, it is the largest endocrine organ in the body. Adipocytes(fat cells) release numerous hormones and other factors thattravel throughout the body signaling the musculoskeletal system,pancreas, liver, heart, adrenal glands, and central nervoussystem.¹ Moreover, in people with excess body fat, adipocytesrelease aberrant factors that can cause or amplify metabolicdisorders. Thus, adipose tissue itself plays a role in causingdiseases such as type 2 diabetes and cardiovascular disease.

In addition to its endocrine function, fat serves as an immuneorgan. Some researchers² argue that fat may be predominantlyan immune organ. The link between obesity and atherosclerosisand other vascular diseases may lie in the immune function ofadipocytes, which is reviewed later in this article. In peoplewho are healthy and of normal weight, fat cells release moleculesthat regulate blood pressure, blood coagulation, and estrogenrelease in postmenopausal women, among other things.³ (Alsosee the related article by Cade⁴ on microvascular and macrovasculardisease in diabetes mellitus in this issue.)

It is now known not only that fat is more than a storage sitefor excess energy but also that obesity is both an enlargementof adipocytes and an increase in the number of adipocytes formedfrom a large pool of precursor stem cells.⁵ Large fat cellsare less sensitive to insulin and exert a higher basal rateof lipolysis, the release of free fatty acids by adipocytes,than small fat cells.⁶

Adipokines are molecules released by fat cells that in manyinstances cause the pathological conditions associated withobesity. The question is: Why would evolution lead humans toa situation in which excessive obesity is encouraged or enhancedby factors that induce chronic inflammation and send aberrantsignals to the brain and muscle? In order to answer that question,one must imagine what life was like for thousands of years whenall creatures had to exist off the land in fluctuating statesof feast or famine. When food was scarce, the body used itsreserves to exist. When food was in abundance, the body releasedspecific molecules (many of them adipokines) to induce fat formationand decrease glucose utilization in the form of short-term insulinresistance.⁷ The energy stored in the fat could be called uponin future times of famine. Insulin resistance was meant to bea temporary state when food was abundant.

Most people in the United States no longer live in a world inwhich food is ever scarce. Therefore, what had at one time beena beneficial adaptation that promoted survival has now becomea curse for the 66% of all American adults who are overweightor obese.⁸ No wonder gaining weight is so easy and losing weightis so difficult: People are genetically programmed to accumulatefat in times of food abundance. The once temporary state ofinsulin resistance meant to help the species survive has nowbecome the permanent state of type 2 diabetes.

This explanation for the high levels of worldwide obesity wasfirst proposed over 40 years ago and was termed the "thrifty"genotype.⁹ One problem with the thrifty gene theory in explainingthe current obesity epidemic is that it predicts that everyperson with an ample food supply should be obese; although thatis certainly the trend,¹⁰ it is not universal. Alternative hypothesesrely on random genetic drift, as opposed to directed selectionof survival genes, to explain the worldwide health care crisisof obesity.¹¹

Adipokines

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Adipokines

Adipokines, the molecules and hormones released by adipocytes,constitute a wondrous category of molecules that are only beginningto be understood and appreciated. At this time, more than 100different adipokines have been shown to be released by fat cells;they include fatty acids, prostaglandins, steroids, and specifichormones that regulate hunger and metabolism.¹ Some of thesefactors act within fat tissue in a paracrine fashion. Otherfactors travel through the bloodstream to distant sites as hormoneswith very specific effects. The following section reviews themajor molecules released by fat cells (Table).

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Table. Major Molecules Released by Adipocytes or Adipose Tissue Macrophages^{^a}

Leptin

The first adipokine identified was a protein—leptin—expressedalmost exclusively in fat cells¹² (Fig. 1). Mice with mutationsin the leptin gene or leptin receptors become extremely obese.Likewise, people with genetic leptin deficiencies are severelyobese and have impaired thermogenesis and insulin resistance;all of these conditions can be reversed if the person is treatedwith leptin replacement therapy.¹³ These findings led to greatenthusiasm for therapeutic leptin as a weight loss drug. Unfortunately,the administration of exogenous leptin to overweight and obesepeople lacking mutations in the leptin gene failed to resultin weight loss because the body rapidly became resistant toleptin given as a drug.¹⁴

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Figure 1. Single fat cells secrete different molecules depending on whether a person is of normal weight or obese. Healthy adipocytes from a person without obesity (illustrated on the left) would secrete low levels of leptin, visfatin, retinol-binding protein 4 (RBP4), and fatty acids. The cells might release small amounts of tumor necrosis factor alpha (TNF- ${alpha}$ ) and resistin. Healthy cells would release large amounts of adiponectin (shown in red). Under states of obesity (illustrated on the right), the same adipocytes would be larger and would release only small amounts of adiponectin but would release high concentrations of leptin, visfatin, RBP4, and fatty acids (shown in red). Large amounts of resistin and TNF- ${alpha}$ would be released from the tissue, but they would likely originate from the macrophages in the fat, not the adipocytes themselves.

Within the body, leptin acts on the central nervous system tosuppress appetite. Receptors for leptin are found in the hypothalamusand provide the normal satiation signal to the brain.¹⁵ Therefore,when excessive fat stores are available, leptin signals thebrain to decrease appetite. Along with decreasing appetite,leptin increases energy consumption,¹⁶ making it a highly desirablehormone. In states of obesity, circulating leptin levels arehigh; therefore, one would assume that appetite would be low,but the brain does not respond normally to chronically highlevels of leptin by decreasing appetite. Instead, the brainreceptors appear to become resistant to high levels of leptin,¹⁷just as overweight people became resistant when given leptinas a drug.¹⁴ Resistance and obesity appear to be significantproblems, as this same process explains why obese and sedentarypeople do not efficiently utilize glucose in their skeletalmuscles. The muscles become resistant to insulin.

In addition to its role in regulating weight, leptin regulatespuberty and reproduction, acting like other growth hormones.This role may explain why overweight adolescent girls with highleptin levels typically experience puberty at an earlier agethan girls of normal weight. A study of adolescent boys foundthat abnormal leptin signaling indicates metabolic irregularitiesat early phases in the disease process, when other tests arestill negative.¹⁸ Thus, a change in leptin levels has been suggestedto be an early plasma marker for predicting metabolic syndrome,at least in adolescents.

Receptors that bind leptin are also expressed throughout thecardiovascular and immune systems.¹⁹ Humans with a rare geneticmutation resulting in a lack of leptin have hyporesponsive Tcells and other immune dysfunctions.¹³ Decreased leptin concentrationshave been associated with immune diseases such as rheumatoidarthritis and intestinal inflammation. Interestingly, a recentarticle linked leptin levels to damaged knee cartilage independentof body mass index (BMI); the authors suggested that the cartilagedamage was hormonally related and that abnormal leptin signalingwas one of the mediators.²⁰

Adiponectin

Adiponectin was first identified by 4 different laboratoriesindependently as an important circulating factor released fromadipocytes.²¹ Adiponectin has several beneficial effects. Ithas a strong anti-inflammatory role and is protective againstvascular diseases and metabolic diseases. It originates fromsubcutaneous fat; less is produced by intra-abdominal fat.²²Adiponectin is unique because, although most adipokines arereleased in higher quantities in states of obesity, adiponectinis released in lower levels in people who are obese comparedwith people of normal weight (Fig. 1).

Adiponectin levels are reduced under conditions of insulin resistance,type 2 diabetes, and cardiovascular disease.²³ Low levels ofadiponectin predict the future development of both type 2 diabetesand cardiovascular disease.^21,24 Low levels also predict weightgain in adolescents as the children move into adulthood.²⁵ Ingeneral, adiponectin levels are higher in women than in men,²⁶and they appear to be associated with ethnicity. African-Americanand Filipino women have significantly lower plasma adiponectinlevels than white women, and those differences are independentof body size or insulin resistance.²⁷ Weight loss results inan increase in circulating adiponectin levels, which is accompaniedby an improvement in insulin sensitivity in skeletal muscle.²³

Adiponectin also is reported to have an antiatheroscleroticeffect, as low levels of adiponectin are associated with coronaryartery disease.²⁸ At normal concentrations, it reduces the expressionof vascular adhesion molecules involved in clot formation.²⁹It also reduces the activity of inflammatory modulators releasedby macrophages, monocytes, and dendritic cells.³⁰ Therefore,it is an important suppressor of inflammation in the vasculature.

Weight loss after gastric bypass surgery increases adiponectinlevels.^31,32 Interestingly, exercise training not accompaniedby weight loss does not result in a change in adiponectin levels.³³Therefore, it appears that the most important parameter fordetermining adiponectin levels is fat, not fitness. Weight loss,as well as fitness, must be integral to designing an exerciseprotocol to return adipokine signaling to healthful levels inobese people.

The therapeutic administration of adiponectin to reverse insulinresistance has been accomplished only in rodent models of diabetes.In animal models of both type 1 and type 2 diabetes, the injectionof adiponectin resulted in significant decreases in blood glucoselevels.³⁴ However, this result has not been successfully repeatedin humans.

Resistin

Resistin was first identified in 2001 as a protein secretedspecifically from adipocytes. It is called resistin becauseit induces insulin resistance in animals.³⁵ Serum resistin levelsare elevated under conditions of obesity, and the infusion ofresistin produces insulin resistance.^36,37 Recent studies inhumans showed a consistent association between resistin andinflammation,^38,39 but a direct link between resistin and insulinresistance in humans is less clear. Although one study showeda link between increased resistin levels and insulin levelsin women who were prediabetic,⁴⁰ other researchers³⁶ speculatedthat this link may occur through actions of leptin on the immunesystem that promote inflammation. Resistin may have the directeffect of promoting insulin resistance only in rodents,¹⁶ andan association with insulin resistance in humans may act throughinflammatory steps.

Also controversial is the site of production of resistin. Originally,it was assumed that adipocytes were secreting resistin, butrecent evidence suggests that it may actually be produced byinflammatory cells in fat⁴¹; this uncertainty is the reasonwhy a question mark was included in Figure 1 for the originof resistin. Much about resistin is yet to be determined, includingwhether it has any direct role in the pathology of type 2 diabetesin humans.

Retinol-Binding Protein 4

Retinol-binding protein 4 (RBP4) was recently discovered duringthe examination of a mouse model with a genetic mutation thatcaused insulin resistance.⁴² Retinol-binding protein 4 is acirculating protein normally responsible for the transport ofvitamin A (retinol). Plasma levels and the expression of thisprotein within adipose tissue are elevated in at least 5 differentmouse models of insulin resistance and obesity.¹ Increased RBP4impairs insulin signaling in muscle, and the normalization ofserum RBP4 levels leads to improved insulin action.⁴³

In humans, plasma RBP4 concentrations are higher under conditionsof impaired glucose tolerance and type 2 diabetes.⁴⁴ This increaseis not associated directly with obesity as measured by eitherBMI⁴¹ or percentage of body fat.⁴⁵ Therefore, although adipocytesproduce RBP4, the increased levels associated with insulin resistanceare independent of fat accumulation.⁴⁶ In exercise-trained subjectswith improved insulin resistance, a reduction in serum RBP4concentrations has been measured.⁴⁷

Tumor Necrosis Factor Alpha

Tumor necrosis factor alpha (TNF- ${alpha}$ ) is a small, secreted proteinproduced by many different types of cells with a variety ofactions. The original reports of TNF- ${alpha}$ expression in obese rodentsand humans appeared in the early and mid 1990s.⁷ In states ofobesity, TNF- ${alpha}$ is produced in high levels, and insulin resistanceensues.⁴⁸ Tumor necrosis factor alpha causes insulin resistanceby inhibiting insulin receptor signaling and has an autocrineeffect on adipose tissue itself.

Recent evidence indicated that adipocytes produce and secreteTNF- ${alpha}$ but that the majority of the molecule associated with obesityis actually produced by macrophages that infiltrate excessivefat.⁴⁹ The macrophages release TNF- ${alpha}$ and other immune molecules,such as interleukins, under conditions of obesity (Fig. 2).Most of the TNF- ${alpha}$ that is released by fat cells is utilized locallyand is not released into the circulation.⁵⁰ Therefore, it hasmore of an autocrine or paracrine effect rather than a trueendocrine effect (Fig. 2).

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Figure 2. Recruited macrophages enter fat under conditions of obesity. Under healthful (nonobese) conditions, adipocytes are small and have few resident macrophages (tan color), which are relatively inactive or release anti-inflammatory molecules (left). Under conditions of obesity, new macrophages (blue) are recruited into the fat tissue and release large amounts of inflammatory molecules (right). Those inflammatory molecules may act at distant sites in the body or may activate the adipocytes in the fat, as shown for tumor necrosis factor alpha (TNF ${alpha}$ ).

In a very interesting study of 188 male subjects with risk factorsfor diabetes or cardiovascular disease, researchers looked forchanges in several adipokines with exercise, changes in diet,or both.⁵¹ They found that only TNF- ${alpha}$ levels decreased with theinterventions and that the decreases occurred when the subjectsunderwent exercise training or when they improved their dietaryintake.⁵¹

Visfatin

Visfatin is one of the most recently discovered adipokines andis so named because it is found at higher levels in visceralfat than in subcutaneous fat or other fat sites. Visfatin isreleased by adipocytes and binds to insulin receptors, stimulatingglucose utilization in peripheral tissues; therefore, it mimicsthe effects of insulin.⁵² High levels of visfatin have beenreported in humans with abdominal obesity.⁵³ Visfatin is releasedby fat cells in response to TNF- ${alpha}$ and other inflammatory markers.⁵⁴Hormones such as insulin, progesterone, and testosterone decreasethe release of visfatin by adipocytes.⁵⁵

Visfatin is likely associated with diseases beyond diabetes.High levels of visfatin are detected in patients with inflammatorybowel disease.¹⁶ Although visfatin is released by adipocytesin response to TNF- ${alpha}$ , it also induces the release of more TNF- ${alpha}$ and interleukin 6 and causes the proliferation of lymphocytes—observationsthat researchers are still trying to interpret but that suggestthat visfatin is closely linked to inflammation.

Other adipokines that are worthy of mention include angiotensinII, interleukins, and free fatty acids. The angiotensinogensignaling pathway is important in vascular control. AngiotensinII is one of the most potent vasoconstrictors produced by thebody and is closely linked to high blood pressure. Interleukin6 is certainly produced by adipocytes, as up to 30% of the totalinterleukin 6 in people who are obese may originate from theirfat cells.⁵⁶ Interleukin 6 may stimulate the movement of macrophagesinto adipose tissue in times of obesity and inflammation. Freefatty acids released by adipokines originally were thought tobe necessary as an energy source, and this is true. However,free fatty acids also can act as endocrine signals and are knownto impair the actions of insulin.⁵⁷ These are merely a few ofthe signaling molecules that are released by fat cells and thatwork locally or travel to distant sites in the body to exerttheir effects.

Exercise and Adipokines

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Exercise and Adipokines

Several studies have shown that aerobic exercise induces acuteeffects or long-term effects on adipokine levels. In contrast,few, if any, studies have specifically examined the effectsof resistive exercises. In general, exercise that is associatedwith weight loss has the most influence on adipokine levels.

A 4-week aerobic exercise program for women resulted in a decreasein leptin levels starting after the first week of the exerciseprotocol; this decrease was maintained throughout the exerciseprogram.⁵⁸ Surprisingly, leptin levels have been shown to changewith exercise independent of weight loss. A group of teenagegirls with type 1 diabetes and normal BMIs were placed in anexercise program. Although leptin levels increased in the nontrainedcontrol group, they remained constant for 6 months in the exercisegroup.⁵⁹

In studies of the effects of exercise on adiponectin, the resultshave been mixed. Studies that have looked for changes in plasmaadiponectin levels have often failed to measure any changeswith exercise.⁶⁰ In men who were lean and men who were overweight,exercise increased local adiponectin concentrations within adiposetissue but did not change plasma adiponectin levels.⁶¹ Exercisepromotes the expression of more adiponectin receptors in skeletalmuscle^62,63; this finding is interesting because adiponectindecreases insulin resistance in skeletal muscle. Therefore,changes in adiponectin should be evaluated first within fatand muscle tissues rather than in plasma.

A 12-week aerobic exercise training program with weight reductioncaused a significant decrease in plasma visfatin levels in womenwithout diabetes.⁶⁴ Because visfatin mimics the action of insulin,it is viewed by some researchers⁵³ as a positive adaptationto prevent further increases in glucose levels under conditionsof obesity.

One study examining changes in resistin levels with exerciseshowed no effects, even when leptin levels were reduced.⁶⁵ Anotherstudy consisting of 16 weeks of exercise training showed significantreductions in plasma resistin levels.⁶⁶ Researchers will continueto sort out the nuances of the effects of exercise on adipocytesignaling; in general, however, exercise moves adipokine releaseto more normal levels in people who are obese. (Also see therelated article by Turcotte and Fisher⁶⁷ in this issue.)

Obesity Is a Chronic State of Inflammation

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Obesity Is a Chronic...

Healthy adipocytes are inundated with vascular cells, neurons,and cells of the immune system. These cells are important insupporting healthy adipose tissue. However, in states of obesity,the immune cells become stimulated by adipokines and other factorsto become overly active. Leptin alone is known to activate macrophagesand helper T cells, increase the maturation and survival ofthymic T cells, increase the release of interleukins, activatedendritic cells, and stimulate the proliferation of naive Tcells.¹⁶ These actions stimulate a robust inflammatory responsewithin fat.

The first concept important to understand is that excess adiposetissue initiates several cellular pathways leading to chronicinflammation. The link between chronic inflammation and obesitywas first proposed in the 1960s, when epidemiology studies indicatedthat obese people had elevated levels of circulating inflammatorymarkers. Since then, the results have been verified, and additionalinflammatory markers have been identified. It was not until1993 that an important article, published in Science, demonstratedthat adipocytes released TNF- ${alpha}$ , resulting in insulin resistance.⁶⁸At the time, TNF- ${alpha}$ was predominantly known to be an inflammatorysignaling molecule. It is now understood that there is a greatdeal of cross talk between the insulin signaling pathway andthe inflammatory pathway in humans. Furthermore, one of themain molecules, if not the most important molecule, involvedin that cross talk is TNF- ${alpha}$ .

The exact mechanism leading from obesity to inflammation isnot clear, but there are several theories. One theory statesthat the larger number of enlarged adipocytes associated withobesity actually causes a local oxygen shortage, triggeringa state of chronic hypoxia and local inflammation in the surroundingcells.⁶⁹ Conversely, it is known that adipocytes themselvescan stimulate inflammatory responses. Locally secreted adipokinessuch as resistin, leptin, and adiponectin attract proinflammatorymacrophages into adipose tissue, where they encircle dying adipocytes(Fig. 2). The macrophages release their own factors that furtherstimulate the inflammatory process.⁷⁰ In addition, obesity oftenis accompanied by increased levels of free fatty acids, whichcould activate proinflammatory responses in blood vessels, fatcells, and immune cells.⁷⁰

As explained earlier, macrophages infiltrate adipose tissueat higher levels in states of obesity. The number of macrophageswithin fat tissue is directly correlated with the amount offat tissue and the size of adipocytes. In states of obesity,50% of the total cellular content in the fat may actually beinflammatory macrophages, whereas in lean people, that percentageis closer to 10%.⁷¹ In states of obesity, new macrophages arerecruited to adipose tissue (Fig. 2). These recruited macrophagesbehave in a manner very different from that of macrophages residingwithin adipose tissue in states of leanness.^72,73 Resident macrophageshave an anti-inflammatory role, whereas macrophages recruitedto adipose tissue under conditions of obesity have a proinflammatoryrole, perhaps because the 2 types of macrophages originate fromdifferent sources.

Therefore, excessive fat cells lead to inflammation. The nextquestion is how the inflammation in fat cells results in insulinresistance. De Luca and Olefsky⁷⁴ proposed a 2-step progressionin which the inflammatory process is first activated by macrophageswithin adipose tissue. Those signals spread in a paracrine fashion,activating inflammation in nearby tissues and resulting in resistanceto insulin signaling in those tissues. Free fatty acids aresubsequently released from stimulated adipocytes, leading tosecondary insulin resistance at distant sites, such as skeletalmuscle.⁷⁴ The actual process is yet to be elucidated.

Stress of Obesity

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Stress of Obesity

It is clear that adipocytes have endocrine and immune functions.Beyond those roles, they are important in maintaining the levelof oxidative stress in the body. Oxidative stress is causedby free oxygen radicals, which are superreactive oxygen molecules.In healthful states, low levels of free oxygen radicals area necessary part of cellular respiration. They are balancedby antioxidants, including dietary products containing vitaminsA, C, and E. In states of obesity, the balance is lost, andexcess free oxygen radicals accumulate in tissues.⁷⁵ Vincentet al⁷⁵ demonstrated that obese people were far less likelyto eat foods rich in antioxidants, such as fruits and vegetables,and suggested that people who are obese "accrue an antioxidantdeficit" because of poor food choices. The introduction of low-fatdiets, high in antioxidant activity, generally resulted in rapiddecreases in oxidative stress biomarkers, even without weightloss.⁷⁵

The body has endogenous antioxidant enzymes that limit freeoxygen radical damage to cells. In the early stages of obesity,these enzymes become more active, ready to battle the obesity-relatedoxidative stress. With chronic obesity, antioxidant enzymesbecome depleted and can no longer maintain the balance.⁷⁶ Incultured adipocytes, oxidative stress induces insulin resistancein individual fat cells, and exposure to antioxidants alleviatesthe resistance.^77,78 Insulin resistance in adipocytes is aninteresting observation, because it indicates that defects inthe adipocytes of people who are chronically obese can no longertake up excess energy in the form of glucose for storage, ultimatelyleading to the hyperglycemia essential to type 2 diabetes.

Although oxidative stress likely does not cause obesity, itcertainly hastens the medical complications associated withobesity, including vascular diseases such as atherosclerosisand high blood pressure and metabolic disorders such as type2 diabetes. It is important to be mindful of this informationwhen prescribing exercise for people who are obese because theyare more susceptible to oxidative stress during an acute boutof exercise than are people of normal weight.⁷⁹ Vigorous exercisehas been associated with more oxidative stress in people whoare obese than has moderate exercise. Although this informationis important, it should not discourage the prescription of exercisefor people who are obese. The positive effects of long-termexercise are clear. Oxidative stress markers were reduced with6 months of exercise even when a person's BMI did not change.^80,81In animal models, lipid peroxidation levels were lower in theskeletal muscle of endurance-trained rats than in that of sedentarycontrol rats.⁸²

All Fat Is Not Equal

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All Fat Is Not...

Although there is a clear link between obesity and insulin resistance,diabetes, and cardiovascular disease, there are people withobesity who have no signs of these disorders. Up to 20% of peopleclassified as obese, with a BMI of greater than 30, have a normalmetabolic profile and normal insulin sensitivity.⁸³ Other studieshave shown that 20% of obese people also have normal cardiovascularprofiles, with no hypertension, normal lipid profiles, and normalglucose tolerance.⁸⁴

Humans show great variability in the distribution of fat. Theheterogeneous nature of fat indicates that different types andlocations of fat have different actions. Since the 1950s, ithas been postulated that abdominal fat is a greater health riskthan subcutaneous fat in other parts of the body, such as thethighs. In the 1980s, clear proof showed that fat on the thighs,typically seen in females, posed less risk for metabolic syndrome.⁸⁵In general, females have more body fat than males, and a greaterpercentage of it is stored in the lower body, with less visceralfat, than in even lean males.⁸⁶ Research showed that when mealswith low fat and high fat contents are compared, females moreefficiently take up the triglycerides from the high-fat mealin their lower-extremity adipose tissue than do males, who typicallystore the triglycerides in the abdominal region.⁸⁷

Within the abdomen, there are subcompartments for fat, includingsubcutaneous, subfascial, and visceral (surrounding organs).Subcutaneous fat is rather benign, but visceral fat around theorgans has been compared with a cancerous tumor, creating pathologicalconditions in nearby tissues (Fig. 3). A very important studypublished in 2005 measured visceral and subcutaneous abdominalfat and compared it with intramuscular and subcutaneous thighfat.⁸⁸ Using computed tomography (CT) scans of more than 3,000people, the researchers found that visceral fat was the mostimportant predictor of the development of metabolic syndrome,even in people of normal weight.⁸⁸ Conversely, subcutaneousfat around the thighs was a negative predictor of metabolicsyndrome.⁸⁸

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Figure 3. Fat distribution within the abdomen varies among people. A cross section of the abdomen shows organs that are relatively near each other in a lean person. With subcutaneous fat (under the skin), the arrangement of the organs is basically undisturbed, with a few adipocytes surrounding the organs (yellow circles). In the presence of large amounts of visceral fat, the organs may be shifted and further apart, with fat surrounding each one. People with normal body mass indexes can have visceral fat; only a computed tomography scan would reveal the visceral fat. However, most people with visceral fat also have excess subcutaneous fat, resulting in central obesity.

Even more telling are studies that monitored people after surgeriesor procedures for weight loss. People who undergo liposuction,which is predominantly the removal of subcutaneous fat, showno improvement in insulin sensitivity or other metabolic syndromefactors after the liposuction.⁸⁹ In contrast, loss of visceralfat through conventional diets is associated with improved insulinsensitivity.^90,91 Weight loss following gastric surgery is associatedwith decreased oxidative stress, improved blood lipid profiles,and decreased levels of proinflammatory markers.⁹² Therefore,fat surrounding the organs, especially the liver, may play asignificant role in the genesis of metabolic syndrome. Suchobservations support the notion that detrimental actions, includinginflammation, associated with adipocytes have dramatic effectson neighboring organs.

When this information is applied clinically, it is obvious thatwaist circumference should be an important measurement takenfor all people who are overweight or obese. Abdominal obesityis now recognized as a greater risk factor than overall obesityfor a number of diseases, including type 2 diabetes and cardiovasculardisease.⁹³ It is more highly associated with high blood pressurethan BMI measurements. Reproducible waist circumference measurementsshould be taken at the high point of the iliac crest. However,a second important measurement is the maximum abdominal circumference.Ethnic and body type differences may cause changes in the distributionof abdominal fat, so that the maximum measurement is not alwaysat the top of the iliac crest.⁹³

Fat in Nonfat Cells

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Fat in Nonfat Cells

Another subtlety in contemplating fat is its accumulation inthe form of lipid droplets in cells that are not adipocytes.Lipid droplets found in nonfat cells are referred to as ectopicfat⁹⁴ and are a normal component of all cells. They providean immediate source of energy for cells. In obesity, the abilityof adipose tissue to store excess calories is impaired becauseadipocytes themselves become insulin resistant; therefore, theycannot take up glucose.⁹⁵ Consequently, ectopic fat accumulatesin the organs and in skeletal muscle.⁹⁶ The abnormal lipid dropletscan cause lipotoxicity and programmed cell death and have beentermed "weapons of lean body mass destruction."⁹⁷ Therefore,in states of obesity, not only do adipocytes (fat body mass)increase in size and number but also the lipotoxicity of nonadipocytescauses a decrease in lean body mass through lipotoxicity-inducedcell death. In a study of the offspring of people with type2 diabetes, boys with normal glucose tolerance were found tohave less ectopic lipid accumulation and less visceral fat thanboys with increased insulin resistance.⁹⁶ Ectopic fat in skeletalmuscle is a strong predictor of type 2 diabetes.⁹⁸

Only recently have researchers begun to recognize that adipokines(adiponectin, leptin, RBP-4, and others) can be produced bynonfat cells when ectopic fat is present, especially in skeletalmuscle and the liver.⁴⁶ These adipokines released within nonfattissues can have dramatic physiological results. The effectsof ectopic fat within specific tissues, such as the heart, pancreas,and liver, are highlighted here. However, Rasouli et al⁹⁴ provideda detailed review of this topic. Lipid accumulation in livercells (hepatocytes) may be among the most dangerous. It is arelatively common condition, termed hepatic steatosis (or fattyliver), and for years was not directly associated with obesity.Steatosis is a combination of adipocytes residing in the liverand excess lipid droplets within and around liver cells. Electronmicrographs of the livers of diabetic rats showed expanded lipiddroplets in those livers as well as a loss of healthy mitochondriawith diabetes (Fig. 4). Liver steatosis is associated with hepaticinsulin resistance and is common in metabolic syndrome. It isa predictor of type 2 diabetes and causes elevated levels ofliver enzymes.⁹⁹ Likewise, lipids can accumulate in pancreaticislet cells, the insulin-producing cells of the body. Excessivelipid droplets there result in cell dysfunction and even celldeath in rodents.¹⁰⁰

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Figure 4. Ectopic lipid droplets in livers of diabetic and control rats. Electron micrographs illustrate lipid accumulation and loss of healthy mitochondria in livers of diabetic rats relative to matched control rats. The lipid droplet (LD) in the liver of a diabetic rat is larger than the lipid droplet in the liver of a nondiabetic rat. The droplet identified in the control liver is located in a healthy cell with abundant, well-formed mitochondria (arrows), whereas the lipid identified in the diabetic liver is located in a dying cell with expanded mitochondria (EM). Other cellular components shown include the nucleus (Nuc) and the endoplasmic reticulum (ER).

Research with diabetic rodents showed an increase in the numberof lipid droplets in cardiac myocytes that was not reversedby endurance exercise training.¹⁰¹ Using a rat model of type2 diabetes, other researchers¹⁰² showed that lipid accumulationin the heart was associated with necrosis of cardiomyocytesand contributed to the functional cardiomyopathy documentedby Loganathan et al.¹⁰³

For physical therapists, lipid deposits in skeletal muscle areinfinitely important. It has been known for a long time thatskeletal muscle health is directly associated with type 2 diabetes.Seventy-five percent of all glucose ingested is utilized, viainsulin, by skeletal muscle,¹⁰⁴ which is why sedentary peopleare at such a high risk for obesity and diabetes. When insulindoes not act normally to move glucose into skeletal muscle,because of aberrations in either insulin receptors or downstreamsignaling molecules, insulin resistance ensues.

Diabetes has been shown to be associated with excess lipid dropletsin the skeletal muscle cells of rats with diabetes.¹⁰⁵ Peoplewith insulin resistance frequently have extra lipid droplets,known as intramyocellular lipids, in their skeletal muscle.¹⁰⁴In fact, the level of lipid accumulation in skeletal muscleis highly correlated with the amount of insulin resistance present.¹⁰⁶This relationship is independent of obesity as measured by waist-to-hipratio, percentage of body fat, or BMI.¹⁰⁷ Women oxidize morelipids during endurance exercise than men, and this higher degreeof fat oxidation is associated with the presence of more lipiddroplets in skeletal muscle.¹⁰⁸

Intramyocellular lipid levels in muscle have been reported todecrease with weight loss, resulting in less insulin resistance.¹⁰⁹The treatment of people with type 2 diabetes with insulin-sensitizingdrugs such as metformin reduces the levels of lipid accumulationin both the liver and skeletal muscle.¹¹⁰ Likewise, people withhigh levels of circulating adiponectin, which is protectiveagainst insulin resistance, have less ectopic fat accumulationin muscle and other tissues.¹¹¹ It appears that weight lossand exercise would benefit skeletal muscle function and decreasethe incidence of type 2 diabetes by reducing the accumulationof ectopic fat in muscle.

A confusing observation is the fact that well-trained enduranceathletes also have high levels of lipid deposits in their skeletalmuscle, just like people who are sedentary and obese. Therefore,endurance athletes and people who are sedentary and obese bothhave elevated levels of intramyocellular triglycerides, butthe first group is very insulin sensitive, whereas the secondgroup is insulin resistant.⁹⁷ Theories abound, but one thatseems more plausible is that, with exercise training, skeletalmuscles need more energy and therefore lipid droplets are moreabundant in muscle cells as a quick source of energy. Metabolismof fatty acids from muscle is extremely sensitive to physicalactivity.¹¹² In an athlete, there would be a continual turnoverof those muscle cell lipid droplets, whereas in a person whois sedentary and obese, the lipid droplets would be incorporatedinto the muscle cells and would remain there. It could be thelong-term storage of those lipid droplets that makes them sensitiveto peroxidation, subsequently releasing damaging by-products,including TNF- ${alpha}$ and the inflammatory molecules discussed earlier.¹¹³Regardless of the mechanism, the conclusions are difficult tooverlook. Exercise is pivotal to fighting diabetes and a varietyof other obesity-related diseases. Skeletal muscle utilizationof glucose during exercise keeps average plasma glucose levelsin check, decreases the risk for insulin resistance, and decreasesectopic fat accumulation. (Also see related articles in thisissue by Hilton et al¹¹⁴ and Marcus et al¹¹⁵ about the infiltrationof fat into the muscle of people with diabetes mellitus.)

Conclusion

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Conclusion

Concepts concerning the role of fat in health and disease arechanging nearly every week. New observations, theories, andempirical data have forced endocrinologists, scientists, immunologists,and the general public to change their long-held beliefs aboutfat. Without question, researchers are only at the beginningof a long scientific journey to an understanding of the linksbetween fat and diabetes, cardiovascular dysfunction, cancer,and a myriad of other diseases.

Some key points to consider are as follows: (1) fat has bothendocrine and immune functions as well as an energy storagefunction; (2) adipokines released by fat cells are beneficialin health unless the body accumulates too much fat (especiallyvisceral), resulting in abnormal signaling that can actuallyincrease the progression of disease; (3) chronic inflammationis present within excess fat tissue and is involved in the progressionto insulin resistance and diabetes; and (4) the anatomical andcellular locations of fat play a role in how fat affects health.

This intriguing story will continue to unfold as the negativeconsequences of obesity overwhelm the health care system. Understandingthe mechanisms involved will help researchers and cliniciansdesign interventions that can lessen the impact. However, themost important interventions will be behavioral changes, includingless sedentary behavior, a task well suited for physical therapists.

Footnotes

The author wishes to acknowledge Dr Yvonne Searls for generouslydonating the liver electron micrographs.

References

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