Adiposopathy – “Sick Fat” a Cardiovascular Disease?


There is a fundamental difference between uncomplicated adiposity defined as excessive adipose tissue and adiposopathy (“sick fat”) defined as anatomically and functionally pathological enlargement adipocyte cells leading to adipose tissue dysfunction. The latter results from positive caloric balance in genetically and environmentally susceptible individuals that result in adverse endocrine and immune responses that may directly promote cardiovascular disease and may worsen or potentiate metabolic disorders. As many of these metabolic disorders are themselves major cardiac risks (type 2 diabetes mellitus; hypertension and dyslipidaemia), adiposopathy therefore indirectly increases cardiovascular disease and vascular damage self-perpetuating the metabolic chaos and end organ damage.

Adiopsopathy is promoted by unhealthy lifestyle including calorie overload and sedentary living in genetically and environmentally predisposed individuals. With impaired adipogenesis of peripheral, sub cutaneous and visceral adipose tissue during positive calorie balance, existing fats cells hypertrophy; increase circulating free fatty acid and lipids depositing in non-adipose tissue such as liver; muscle; pancreas and the heart resulting in lipotoxicity. The adiposopathic endocrine and immune dysfunction directly contribute to the pathophysiology of the cardiovascular system disease and of the organ dysfunction.

Adipose Tissue Anatomy, Embryology and Adiopogenesis:

Fat-containing adipocyte constitutes the majority of adipose tissue cellular content. Adipocytes are surrounded by fibrous connective tissue, collagen, nerves and blood vessels termed the supporting stromal network including fibroblasts, preadipocytes, endothelial precursor cells, smooth muscles cells, blood vessels cells and immune cells. Interestingly adipose tissue, the stromal network and surrounding tissues and organs share a common lineage from the mesoderm of the zygote. The mesenchymal stem cells may differentiate into skeletal myoblasts, osteoblasts, chondroblasts, marrow stromal cells, neuron-like cells, cardiomyocytes, angiocytes and adipocytes.

With progressive adiposopathy there appears to be neuro endocrine “cross-talk” from the “sick fat” to the other mesodermal and endodermal derived tissues and accounts for the multisystem organ and tissue disorders in obesity, metabolic syndrome and type 2 diabetes mellitus.

Conversely adipose tissue is a rich, non-embryonic source of mesenchymal cells whose relative ease in accessibility and capacity for differentiating into heart, and blood vessel cells has direct medical applications to cardiovascular disease regenerative medicine, tissue engineering and cell replacement therapies as potential therapeutic modality to repair post ischaemic or other cardiomyopathies.

Previously, adipogenesis was thought to cease early in life, resulting in a fixed number of adipocytes that predestined individuals to be lean or obese. However, fat-cell turnover is now known to be a dynamic process by which mesenchymal stem cells undergo lineage commitment, pre-adipocyte proliferation, growth arrest, and terminal differentiation into mature adipocytes. The number of adipocytes is therefore dependent on the balance between adipogenesis and apoptosis with some suggesting that approximately 10% of fat cells are renewed annually at all adult ages and at all levels of body mass index (BMI). This has clinical implications because during positive caloric balance, adipocytes normally undergo initial hypertrophy, which elicits cellular signaling for the recruitment, proliferation, and differentiation of new fat cells. If adipogenesis proceeds normally in peripheral subcutaneous adipose tissue, then adiposity may not cause demonstrable adipose tissue dysfunction or adverse metabolic consequences. Conversely, if adipogenesis is impaired, then the lack of adipocytes to adequately proliferate (or differentiate) causes existing cells to undergo excessive hypertrophy, causing adipocyte dysfunction and pathogenic adipocyte and adipose tissue endocrine and immune responses.

The concept of adipocyte hypertrophy during positive caloric balance representing a failure of adipocytes to adequately proliferate is supported by findings that T2DM is associated with a decrease in adipogenic gene expression and that T2DM patients have larger adipocyte size but decreased adipocyte cellularity compared with obese patients without T2DM. In short, if during positive caloric balance, any stage of the adipogenic processes is impaired (recruitment, proliferation or differentiation) then this may lead to pathologic adipose tissue endocrine and immune responses that contribute to metabolic disease, particularly in individuals who are genetically or environmentally predisposed.

Fat Depots:

The clinical importance of adiposity is not only how fat is stored (i.e., adipocyte proliferation vs. adipocyte hypertrophy), but also where fat is stored. Visceral adipose tissue (VAT) may be more metabolically active than subcutaneous adipose tissue (SAT), and these depots inherently differ in processes involving lipolysis/lipogenesis, expression of adipocyte receptors, and differ in the secretion of adipokines/cytokines, enzymes, hormones, immune molecules, proteins, and other factors. Derangements in adipose tissue endocrine and immune processes contribute to metabolic disease. Fat depots other than VAT have pathogenic potential. Pericardial, subcutaneous abdominal, perimuscular, perivascular, orbital, and paraosseal fat depots also have lipolytic and inflammatory activities.

Pericardial and perivascular adiposopathy may have direct pathogenic effects on the myocardium, coronary arteries, and peripheral vessels via dysregulated local secretion of vasoactive and inflammatory factors that may contribute to atheroma instability and other cardiovascular pathophysiology. Pericardial adiposity is strongly associated with coronary atherosclerosis in African-Americans with T2DM, which may contribute to ethnic disparities in atherosclerosis susceptibility. Finally, although often assumed that atherosclerosis is exclusively an intraluminal, subendothelial, lipid-mediated process, pathogenic pericardial and perivascular adipose tissue may directly contribute to atherosclerosis through an “outside to inside” inflammatory atherogenic model, which is again supported by the strong association between pericardial adipose tissue and coronary artery calcification.

Extracellular Matrix Remodeling, Angiogenesis, and Hypoxia:

In addition to how fat is stored and where fat is stored, other determinants of the pathogenic potential of expanding adipose tissue include the interdependent physiologic processes of angiogenesis and extracellular matrix (ECM) remodeling. If an increase in fat storage results in excessive adipocyte enlargement, then adipocyte hypertrophy may contribute to intracellular hypoxia. Additionally, when fat accumulation outpaces angiogenesis, then a relative lack of blood flow may result in both cellular and adipose tissue hypoxia. As with other body tissues (heart), cellular and tissue adipose hypoxia contributes to cellular and organ dysfunction, contributes to pro-inflammatory responses, and all may contribute to the onset or worsening of metabolic disease. For example, if periadipose ECM remodeling is impaired due to relative hypoxia or other adipocyte dysfunction, then further fat storage may be physically limited, resulting in increased circulating free fatty acids and lipotoxicity. Furthermore, hypoxia-driven inflammation may promote ECM instability, and excessive synthesis of ECM components may impose long-term interference with cell–cell contact and adipogenic signaling mechanisms, and thus persistent adverse cellular responses even after weight loss.

Free Fatty Acids and Lipotoxicity:

If during positive caloric balance, adipocytes are unable to store excess energy (mostly in the form of triglycerides), then circulating free fatty acids are increased, causing pathologic disruption of nonadipose tissue organs, such as the liver, muscle, pancreas, and blood vessels. Potential adverse metabolic consequences of lipotoxicity include abnormalities of glucose (Insulin resistance) and lipid metabolism, and high blood pressure. Although VAT is most recognized as a contributor to metabolic disease, the majority of circulating free fatty acids actually originates from SAT, mainly because SAT is the largest fat depot, constituting ~80% or more of total body fat. Even within large vessel drainage of VAT (which sometimes constitutes ~20% of body fat), the majority of free fatty acids in the portal system may originate within SAT, which may contribute to lipotoxic effects on the liver, with adverse clinical consequences such as hyperglycemia and dyslipidemia.

So while VAT is generally considered among the most pathogenic fat depots, if SAT fat storage is limited or impaired during positive caloric balance and if SAT net free fatty acid release is increased into the circulation, then this SAT dysfunction may adversely affect nonhepatic organs, resulting in lipotoxicity to muscle (exacerbating insulin resistance) and the pancreas (possibly reducing insulin secretion).

Adipose Tissue as an Active Endocrine and Immune Organ:

Excessive adipocyte hypertrophy disrupts the normal physiological function of fat-cell organelles (causing adipocytes to become “sick”), as evidenced by increased markers of intracellular endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The ER is a network of interconnected tubules, vesicles, and cisternae that, among other functions, produce protein and lipids and transport proteins and carbohydrates necessary for normal cellular function. Increased markers of adipocyte ER stress are associated with inflammation, cellular dysfunction, and metabolic disease. Mitochondria are membrane-enclosed organelles that contain enzymes responsible for transforming nutrients into cellular energy through the production of adenosine triphosphate. Increased markers of adipocyte mitochondrial stress are associated with obesity, insulin resistance, and T2DM. Among the adverse consequences of adiposity-induced “sick fat” is a disruption of physiological endocrine and immune function, which, in turn, contributes to metabolic disease. The mechanisms by which adiposopathic endocrine and immune responses contribute to T2DM, high blood pressure, dyslipidemia, and other metabolic disorders, and mechanisms explaining how nutrition, physical activity, drug therapies, and bariatric surgical interventions improve metabolic disease.

Adiposopathy and Aging:

Irrespective of age, adiposopathy increases the prevalence of metabolic disease and CVD risk factors. However, adiposopathy and aging share analogous pathophysiology. From a cellular standpoint, both adiposopathy and aging can increase markers of intracellular stress and mitochondrial dysfunction, and both are associated with impaired adipogenesis.

From a clinical standpoint, both adiposopathy and aging:

  • are risk factors for CVD, T2DM, high blood pressure, and dyslipidemia
  • promote endocrinopathies, such as increased free fatty acids and reduced testosterone levels in men
  • both may promote immunopathies such as increased C-reactive protein.

When stratified based on age and BMI, the relationship between adiposopathy and aging is complex, as evidenced by the variable association of metabolic syndrome components. Adverse oxidative reactions are also shared by adiposopathy and aging. Oxidation creates unstable oxygen free radicals and other reactive oxygen species that create biomolecular instabilities toxic to cells. If reactive oxygen species production exceeds a biological system’s ability to detoxify them, then this “oxidative stress” may contribute to metabolic disease and atherosclerosis.

Adiposopathy as a Conceptual Resolution of the Obesity Paradox:

Various obesity paradoxes are described when increased body fat mass does not increase morbidity or mortality, when a decrease in excessive body fat does not improve patient health, or when an increase in body fat mass actually reduces morbidity or mortality. Many of these apparent clinical contradictions are mitigated if the pathogenic potential of excess adipose tissue is assessed not solely by adiposity, but also by adiposopathy.

Not all obesity paradoxes are due to adiposopathy. However, many obesity paradoxes are less paradoxical if adipose tissue is accepted as being more than an inert storage organ. For example, not all overweight patients develop metabolic disease and not all patients with metabolic disease are overweight. This paradox is best explained when understanding that fat weight gain most often contributes to the onset or worsening of metabolic disease when accompanied by pathogenic adipocyte and adipose tissue anatomic, endocrine, and immune responses in genetically and environmentally susceptible patients.

This also helps explain paradoxical populations described as “metabolically healthy, but obese”, “metabolically obese, normal weight”.

Cardiovascular Risk Paradox:

The susceptibility to adiposopathy provides an explanation for the high prevalence of T2DM, the metabolic syndrome, and CVD among Asians, particularly those from the South and East Asian subcontinent. Asian Indians have an increased adipocyte size, fewer adipocytes, increased visceral adiposity, increased circulating free fatty acids, increased leptin levels, increased pro-inflammatory factors (e.g., increased C-reactive protein levels), and decreased anti-inflammatory factors (e.g., decreased adiponectin), which lead to increased insulin resistance and increased CVD risk. Genetic susceptibility helps account for the common clinical finding that many patients of Asian descent have metabolic disease, even when not markedly overweight.

This has prompted international organizations to suggest that Asians should have different cutoff points for the determination of overweight and obesity.

Similarly, adiposopathy helps explain why, for the same age and weight, men have higher rate of CVD compared with women. During positive caloric balance, men often expand lower body fat through the more pathogenic process of adipocyte hypertrophy, whereas women typically undergo the less pathogenic process of adipocyte hyperplasia. Furthermore, men often store excessive fat in an “android” or “apple” (i.e., visceral) distribution, whereas women often store fat in a “gynoid” or “pear” (i.e., peripheral subcutaneous) distribution. These differences in adipose tissue expansion and fat depot accumulation may help explain the sex paradox, in which, when corrected for various demographic factors (such as age), men have higher CVD risk than women.

Cardiovascular Event and Cardiac Procedure Paradox:

Modestly overweight individuals may live longer than those who weigh less, possibly because patients with reduced body weight often have illnesses with high mortality (e.g., chronic heart disease, cancer). However, studies have consistently suggested that modestly overweight patients have reduced morbidity and mortality after diagnosis of CVD, after experiencing a CVD event, and/or after undergoing CVD procedures. This CVD paradox may be risk factor dependent.

Regarding the CVD risk factor of sedentary lifestyle, overweight and obese men may have increased longevity only if they are physically fit. Cigarette smoking reduces body weight, but is a major CVD risk factor. CVD patients who smoke have an increase in all-cause mortality compared with those who quit smoking, especially if they have chronic lung disease, which would tend to further decrease body weight. Thus, despite lower body weight in cigarette smokers, their CVD risk is increased.

Patients with chronic heart failure may have no survival benefit with obesity if they have the major CVD risk factor of T2DM. Most CVD patients have “normal” or only modest elevations in cholesterol (another CVD risk factor); yet have a high prevalence of other adiposopathy-associated CVD risk factors. But, although the CVD associated with the adiposopathy-related CVD risk factors may be more frequent, the morbidity and mortality associated with non-adiposopathy-related CVD pathology may be more clinically adverse. In other words, many patients with genetic dyslipidemia (e.g., familial hypercholesterolemia) are not overweight, yet have a disproportionately high rate of premature cardiovascular morbidity and mortality.

Thus, although adiposopathy-induced CVD may be more common, the morbidity and mortality with non-adiposopathy-induced CVD may be much worse. Finally, mortality among those with CVD is directly associated with central obesity and inversely associated with BMI. Given that central or visceral adiposity is an anatomic manifestation of “sick fat,” this supports the concept that adiposopathy may be a more rational treatment target than adiposity alone.

Finally, adiposity may be associated with enhanced cardiovascular autoreparative potential. Overweight individuals may have greater availability of adipose tissue-associated mesenchymal cells that upon release could conceivably reduce CVD morbidity. After an acute CVD event, reparative circulating mesenchymal cells (originating from tissues such as adipose tissue, bone marrow, and blood vessels) migrate to the injured myocardial site. In their naïve state, adult stem cells may have a limited reparative benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification through guided cardiopoiesis may be needed to optimize therapeutic outcomes. Adiposity signaling promotes the recruitment of adipocytes from adipose tissue-associate mesenchymal cells.

Thus, the presence of adiposity may promote an increased number of progenitor cells available for mobilization into the circulation and potentially enhance adipose tissue mesenchymal differentiation into cells more apt to undergo either cardiopoiesis or adipogenesis (i.e., not yet solely committed to adipogenesis). If so, then an increase in the circulatory release of mesenchymal cells during cardiac injury (or possibly cardiac procedures) might have a greater potential for cardiovascular auto repair. Supporting this mechanism is that abnormally expanded fat tissue increases the mobilization of endothelial progenitor cells, which may have a protective effect against vascular atherosclerosis in obese patients.

Cardiovascular Clinical Trial Paradox:

Adiposopathy may also help explain why overweight patients with elevated markers of inflammation and no major cardiovascular risk factors may, paradoxically, not be “healthy.” The JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial was a landmark CVD outcome trial of 17,802 “apparently healthy men and women” with low-density lipoprotein cholesterol levels < 3.3mmol/l and high-sensitivity C-reactive protein levels ≥2.0 mg/l who were randomized to rosuvastatin (Crestor) 20 mg/day or placebo. The conclusion was that rosuvastatin significantly reduced CVD in “apparently healthy persons without hyperlipidemia but with elevated high sensitivity C-reactive protein levels”.

However, baseline median BMI was ~28 kg/m2 (a BMI ≥25 kg/m2 is considered overweight; a BMI ≥27 mg/m2 with co morbidity is a cutoff point to consider weight-loss drug therapy). Also at baseline, metabolic syndrome was present in 41% of study participants.

One interpretation of the study results was that elevated C-reactive protein is not only a marker of vascular inflammation, but also plays a direct role in the pathogenesis of atherosclerosis and thrombosis. An alternative interpretation is that adiposopathy (a “disease”) was present at baseline in many study participants, as supported by the high mean BMI, the high percentage of study participants with metabolic syndrome, and the elevated C-reactive protein. The latter is supported by the findings that C-reactive protein may be directly released from adipose tissue. Perhaps more importantly, excessive body fat increases adipose tissue release of interleukin-6, which stimulates increased C-reactive protein production from the liver.

It seems plausible that the increased C-reactive protein level found among many JUPITER study participants was significantly due to pathogenic adipose tissue immune responses. Thus, within the adiposopathic paradigm, many of the study participants were not “healthy persons.” Many study participants had evidence of adiposopathy, which may directly and indirectly promote CVD. Finally, it is of interest that a reduction in inflammatory markers (e.g., interleukin-6, C-reactive protein) with statins may, in part, be due to statin-induced reductions in adipose tissue inflammation.


Adiposopathy or “sick fat” is a cardiovascular disease and requires novel solutions to reverse the pathology.

I believe ‘keto-adaptation” with low carbohydrate diets coupled with exercise is possibly the solution. A study has recently been published on the efficacy of carbohydrate restricted diets < 20 g/d in T2DM patients poorly controlled despite combination therapy with Metformin; Insulin and Liraglutide therapy, on metabolic control.

Nearly all participating patients experienced a significant drop in HbA1c at 6 months with 71% reaching the ideal goal of 7.0% . The average mass reduction after 6 months was 10% with most patients satisfied with this form of therapy.

Cheers and Blessings


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