OBESITY AS A CHRONIC DISEASE CONCEPT: PRIDE OR PREJUDICE?
Ramon F. Abarquez, Jr., MD, EFACC, FAsCC, FPCP, FPCC, CSPSH
Professor Emeritus, College of Medicine, University of the Philippines
System Academician, National Academy of Science and Technology
Chair, PMA Continuing Medical Education Commission
Member, Continuing Professional Development Council, PRC Board of Medicine
Unlike hypertension, dyslipidemia, diabetes among other ‘risk profile,’ dependent on specific
diagnostics for detection, the onslaught of obesity like cigarette smoking is obvious to the ‘at-risk’
person. Third party confirmation is clearly easy, at no cost. However, unlike active or passive cigarette
smoking, mostly during ambulatory years of life, that can confer target organ damage (TOD), obesity can
provide direct not indirect, from ‘womb to tomb’, consequences. Anent such chronic impact, could
obesity be a lingering disease? On the other hand, both cigarette smoking and obesity confer ‘pride or
prejudice’ not only in the case in point but to the family members as well. Under such situations,
lifestyle modification is a ‘family affair,’ since behavioral changes would be difficult, if not an outright
sure failure, if other family will behave otherwise.
With or without TOD, unhealthy fat (adiposopathy) related symptoms of sexual dysfunction,
sleep apnea, depression, insulin resistance or osteoarthritis can interfere with weight modification
management. (Gonzalez-Campoy, Int J Endocrinol. 2014;2014:917813.may 12) With such co-morbidities,
some obese patients believe that their metabolic fate is unavoidable, irrespective of intervention. A
‘defeatist belief’ or prejudice perception imply that they will always gain fat mass, even if they reduce
caloric consumption or increase energy loss. “In order for calories to decrease while mass continues to
increase would necessitate that the speed of light decrease respective to the obese patient”, a general
relativity and space time viewpoint. Such, “is seemingly ridiculous, except to the frustrated obese
patient”. (Bays, Expert Rev Cardiovasc Ther. 2005;3:393–404) Thus, the challenge is how to bridge the
frustration or prejudice and highlight the benefits of outcomes or the pride. That is the ‘heart of the
problem’.
CARDIAC ADIPOSITY: The largest fat deposits are in the subepicardial regions adjacent to the coronary
arteries. Based on the “heart too fat to sink”, necropsy analysis, fat is deposited in the right ventricular atrial walls, atrial septum and less frequently in the left atrial wall, rarely in the ventricular septum but
commonly in areas of scarring in the left ventricular free wall. (Shirani, J Am Coll Cardiol 1993;22(1):226–
238. Roberts. Am J Geriatr Cardiol 2000;9(6):347–35) Notably, visceral obesity is the best predictor of
epicardial and pericardial fat among abdominally obese subjects. (Graner, J Clin Endocrinol Metab. 2013
Mar;98(3):1189-97) What is the clinical relevance of cardiac-liposity?
To assess whether epicardial fat volume (EFV), myocardial triglyceride TG content (MTGC) and ectopic
fat depots are linked to metabolic disorders or myocardial function, was the basis of cardiac MRI
diagnostic testing among 63 subjects with normal LV function and no CAD, (33 lean with BMI: 21.4 ± 2.0
kg m(-2)) and 30 obese with BMI: 41.8 ± 6 kg m(-2)) patients. EFV was higher among diabetic obese
versus non-diabetic obese subjects. EFV and MTGC were both associated with parameters of lipid profile
or inflammation (TGs, CRP). Only visceral adipose tissue (VAT) remained independently associated with
metabolic parameters (P<0.01). MTGC was the only parameter independently associated with LV stroke
volume (β=-0.38, P=0.01), suggestive of cardiac steatosis. (Gaborit, Int J Obes (Lond). 2012
Mar;36(3):422-30).
However, fat distributed accumulation is still proportional to the degree of obesity, i.e. body fat (14 to
33 kg), visceral fat (0.8 to 1.8 kg) and cardiac fat (134 to 236 g). Most cardiac fat (70% on average) is
extra-pericardial versus epicardial depot. Only visceral and extra-pericardial fat could discriminate
between subjects with three or more factors of the metabolic syndrome or medium-to-high coronary
heart disease risk score. On multivariable analysis, the best marker of reduced insulin sensitivity was
visceral fat. Extra-pericardial fat was the closest associate of increased blood pressure. Thus, increased
epicardial fat per se does not necessarily translate into presence or prediction of disease. More
importantly, increased deposition of visceral abdominal and extra-pericardial mediastinal fat are both
related to increased triglycerides and with an enhanced cardiovascular disease risk profile.(Seroni,
Diabet Med. 2012 May;29(5):622-7)
However, all three fat deposits, epicardial, pericardial and visceral, are greater in the MetS than
in the control group (p <0.001). The amount of epicardial and pericardial fat correlated inversely with LV
diastolic function. In MetS, accumulation of epicardial and pericardial fat is linked to the severity of
structural and functional alterations of the heart. (Nyman, J Cardiovasc Magn Reson. 2013 Nov
14;15:103)
CARDIAC ADIPOSOPATHY: In a unifying mechanistic concept, adipose tissue is considered to be a huge
gland producing paracrine and endocrine hormones, the adipo(cyto)kines that link obesity to
cardiovascular diseases. The excessive adipocyte hypertrophy in obesity induces hypoxia in adipose
tissue (adiposopathy), converting "healthy" adipose tissue into "sick" adipose tissue. This change in the
profile of reduced "healthy" adipo(cyto)kines (adiponectin) and more release of the "unhealthy"
adipo(cyto)kines, ultimately contribute to the development of cardiovascular diseases, since the heart
and blood vessels are surrounded by epicardial and perivascular adipose tissues.
Adipose tissues can maintain cardiovascular homeostasis by secreting a number of biologically active
molecules, termed "adipokines," as an important component of the 'adipo-cardiovascular axis'
mediating the cross talk between adipose tissues, the heart, and the vasculature. Most adipokines are
proinflammatory and being associated with endothelial and cardiac dysfunction. However, adiponectin
is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular
disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production
of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular
disease. (Xu, Am J Physiol Heart Circ Physiol. 2012 Mar 15;302(6):H1231-40) Thus, ‘adipo-cardiovascular
axis’ among the ‘prejudice’ obese subjects have enlarged adipose tissue infiltrated with activated
macrophages and augmented production of proinflammatory adipokines (TNF-, IL-6, monocyte
chemoattractant protein (MCP)-1, resistin, leptin, lipocalin-2, adipocyte fatty acid binding protein (AFABP), and plasminogen activator inhibitor-1). By contrast, the obese ‘pride’ is the production of
adiponectin, which exerts beneficial effects on insulin sensitivity and cardiovascular function. (Xu, Am J
Physiol Heart Circ Physiol. 2012 Mar 15;302(6):H1231-40)
OBESITY PARADOXES:
ANATOMIC? A review article on obesity paradoxes suggests that during excessive caloric intake, positive
subcutaneous adipose tissue proliferation and differentiation distributes energy overflow. Contrariwise,
negative proliferation and differentiation despite excess caloric intakes can produce “acquired
lipodystrophy” wherein free fatty acids circulates and promotes other fat depots (visceral adipose
tissues, pericardial and perivascular fats) Thus, fat distribution identifies the “anatomic obesity
paradox”. (Bays, Curr Atheroscler Rep (2014) 16:409) Liver, muscle, pancreas, heart and kidney
lipotoxicity can also occur. (Lim, Int J Cardiol. 2013;169:166–76)
PHYSIOLOGIC? Proliferation of smaller, more functional adipocytes that secret anti-inflammatory
adipokines (adiponectin), patients can develop benign multiple symmetrical lipomatosis without
hyperglycemia or dyslipidemia. (Chen, Ann Nutr Metab. 2010;57:68–73). Conversely, inherited
lipodystrophy despite limited body fat storage, with low adiponectin levels have, increased circulating
free fatty acid levels, thereby promoting lipotoxicity towards nonadipose body organs with
hypertriglyceridemia and hyperglycemia (Vigoroux, Int J Biochem Cell Biol. 2011;43:862–76.). If fat
amount is the only consideration and in the genetic context of fat function/dysfunction, patients can be
described as “metabolically healthy, but obese,” or “metabolically obese, but normal weight.” Thus,
such identify the “physiologic obesity paradoxes”. (Bays, Expert Rev Cardiovasc Ther. 2008;6:343–68.)
DEMOGRAPHIC? Women have a “paradoxical” age-adjusted reduced risk of CVD, compared with men,
due to increased proliferation and differentiation of subcutaneous fat cells (“pear distribution”).
(McCarty, Med Hypotheses. 2003;61:173–6.) However, more limited proliferation and differentiation of
subcutaneous fat cells in men, result in more pathogenic visceral fats accumulation (“apple
distribution”) (Karastergiou, Biol Sex Differ. 2012;3:13). Asians typically have fewer adipocytes. But,
increased adipocyte size, increased amount of visceral fat, increased circulating free fatty acid levels,
elevated leptin levels, increased levels of proinflammatory factors (C-reactive protein), and decreased
levels of anti-inflammatory factors (adiponectin) account for worsening metabolic abnormalities and
increased CVD risk despite lesser overweight, a “demographic obesity paradox”. (Bays, J Am Coll Cardiol.
2011;57:2461–73.)
INTERVENTIONAL? If prognosis is fat function based rather than fat mass, liposuction of functional
subcutaneous fat would not be expected to improve, and in fact does not improve, CVD risk factors.
(Klein, N Engl JMed. 2004;350:2549–57). “Intervention obesity paradox” refers to more favorable
outcomes observed among obese patients with a CVD event, or undergoing a cardiovascular procedure
versus lean individuals with or without severe illnesses. On the other hand, the thinner individuals
smoking cigarettes that could not only reduce body weight, but would also increase CVD and mortality
risks. (Blum, Isr Med Assoc J. 2011;13:672–5). Furthermore, obese men may have reduced mortality only
if they are physically fit (Lavie, Mayo Clin Proc. 2013;88:251–8) Those with chronic heart failure may
have no mortality benefit if diabetic, in fact, even among nonsmoking diabetics. (Adamopoulos, Eur J
Heart Fail. 2011;13:200–6) However, a J-shaped association between BMI and mortality among
those who had ever smoked and a direct linear relationship among those who had never smoked. No
obesity paradox is seen among overweight and/or obesity diabetics who may have increased mortality
compared with normal weight diabetics. Therapeutic confounders may be operative as well if obese
cases are also treated with statins, antihypertensive agents, anti-thrombotic agents which are proven to
reduce CVD morbidity and mortality rates. (Tobias, N Engl J Med. 2014;370:233–44).
Pathologic mechanisms can account for CVD in thinner patients who may be more pathologically
vulnerable. Nonetheless, CVD of thinner patients may reflect more aggressive genetic/environmentally
mediated diseases. After an acute CVD event or cardiovascular procedure, circulating stem or
progenitor cells derived from adipose tissue may migrate to the disrupted or injured myocardial or
vascular site since overweight or obesity persons have greater mobilization of progenitor cells into the
circulation compared with thinner individuals (Bellows, Obesity (Silver Spring). 2011;19:1722–6.). Such
cells can, thereby, provide self-repair and improved CVD outcomes (Kollar, Int J Cell Biol. 2009;:904682)
However, stem cell hypothesis is still experimental since cell processing procedures remain secrets.
The obesity treatment paradox is the apparent lack of improved CVD outcomes with weight reduction in
patients who are overweight or obese. The Look AHEAD (Action for Health in Diabetes) 8 years study
among overweight or obesity DM cases showed that ‘Intensive therapy group’ lost more weight, had
lower HbA1c levels and required fewer medications but CVD was not reduced. (Wing, Obesity (Silver
Spring). 2014;22:5–13.). Thus, intensive behavioral and lifestyle weight loss interventions are effective in
treating adiposopathy by improving metabolic parameters except CVD reduction. A notable exception is
bariatric surgery, wherein with weight loss, favorable hormonal/inflammatory effects, is reported to
improve metabolic disease and may also decrease CVD morbidity and mortality. (Moustarah, Curr
Atheroscler Rep.2012;14:588–96.). This supports “sick fat” as a surgical disease. (Bays, Int J Clin Pract.
2009;63:1285–300.).
SUMMARY: Adipocytes are no longer considered just as fat cells related to energy storage and
thermoregulation but cells releasing paracrine and endocrine biologically active molecules, particularly
perivascular adipose tissue (PVAT) surrounding almost all blood vessels. PVAT secretes adipo(cyto)kines
that can easily influence vascular smooth muscle cells. Normal healthy PVAT, in lean subjects, helps to
keep the blood vessels dilated. Obesity is associated with an increased mass in PVAT (adipocyte
hypertrophy) as "adiposopathy" wherein PVAT attracts macrophages and becomes a more inflammatory
phenotype, resulting in a decreased vasorelaxing effect of PVAT, which may be linked to obesity-induced
hypertension, with smooth muscle cell migration and proliferation and the development of
atherosclerotic lesions. (Van de Voorde, Curr Vasc Pharmacol. 2014 May;12(3):403-11.)
So therefore, fat cells or adipocytes being not merely in the fatty liver, subcutaneous ‘innocent’ fats
(adiposity) or visceral ‘unhealthy’ fat (adiposopathy), but more importantly as perivascular, cardiac and
pericardial regions, obesity then should be upgraded from risk to disease, occurring from womb-totomb. Thus, several leading organizations (American Association of Clinical Endocrinologists, National
Lipid Association, Obesity Society, American College of Cardiology, American Heart Association,
American Society of Bariatric Physicians and the National Diabetes Education Program) have all issued
statements calling for the treatment of obesity as a chronic disease. And the American Medical
Association (AMA) finally recognized obesity as a CHRONIC DISEASE at the annual meeting of the House
of Delegates in Chicago, in June 2013.
Thus, obesity as a disease merits bigger, wider and multi-disciplinary attention and commitment being
upgraded to the CAD target organ systemic level despite being tagged as a symbol of affluence, success
or society status. No longer with a cosmetic orientation requiring ‘plastic’ interventions, being a chronic
disease, obesity is the ‘pride’ of the elderly and the survivors of other chronic ailments. However,
obesity from infancy to adulthood, is the ‘prejudice’ of the unfit, lazy, depressed, sleep apnea,
osteoarthritic, or any morbid combination. Therefore, is obesity a mythical, misty or missed mission?
And, what should be the quantifiable ‘pride or prejudice’ outcome based performance evaluation?