|Year : 2014 | Volume
| Issue : 1 | Page : 30-38
Ectopic fat: The potential target for obesity management
Department of Medicine, Obesity and Lifestyle Diseases Clinic, Institute of Post Graduate Medical Education & Research, SSKM Hospital, Kolkata, West Bengal, India
|Date of Submission||20-Oct-2013|
|Date of Decision||30-Oct-2013|
|Date of Acceptance||15-Nov-2013|
|Date of Web Publication||30-Dec-2013|
Department of Medicine, Obesity and Lifestyle Diseases Clinic, Institute of Post Graduate Medical Education & Research, SSKM Hospital, Kolkata 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
Accumulation of fat at ectopic sites rather than mere increase in body fat can explain almost all metabolic consequences of obesity. Certain characteristics of adipocytes like increased size and ectopic accumulation make them metabolically sick. Hence 'adiposopathy' seems to be more important than just 'adiposity'. Genetic and epigenetic factors, along with intra-uterine factors determine ectopic fat accumulation. These three factors result in low subcutaneous adipose tissue (SAT) volume leading to 'spillover' of excess fat to ectopic sites; determining 'metabolic economy', by creating a 'thrifty phenotype' with calorie excess later in life resulting in 'maladaptation' and excess weight gain. This is particularly important for South Asians who have been found to have low SAT volume and possess a 'thrifty phenotype'. Obesogenic diet and lack of physical activity contribute to ectopic fat deposition by creating a positive energy balance. Increased fructose and trans-fat consumption are important determinants of obesity and ectopic fat deposition. The good news is that ectopic fat is very responsive to treatment, disappearing at a faster rate with minimal weight loss, resulting in improvement in metabolic and organ functions. Physical activity causes negative energy balance and improves 'metabolic flexibility'. Targeting 'ectopic fat' should be the highlight of obesity management today and its primordial prevention should aim at targeting maternal nutrition.
Keywords: Adiposopathy, ectopic fat, fat storage, large adipocyte, sick fat, visceral fat
|How to cite this article:|
Ghosh S. Ectopic fat: The potential target for obesity management. J Obes Metab Res 2014;1:30-8
| Introduction|| |
All the branches of medicine have advanced greatly to the molecular level today for better understanding of science. Similarly, obesity medicine has undergone vast changes in understanding. At the clinics, it should not be judged looking only at external measurements, overlooking the basis of its internal effects.
Mere increase in adiposity does not explain all the ill-effects of obesity as exemplified by two significant groups of individuals - the metabolically obese normal weight (MONW) and metabolically healthy obese. It seems that 'ectopic fat' gives a better explanation to this greatest 'obesity paradox'. Ectopic fat, which is the storage of fat in non-physiological sites, is the greatest determinant of all metabolic complications of obesity.
| New Definition of Obesity|| |
An appropriate definition of obesity today must include 'excess' adiposity with 'ectopic' fat deposition in non-adipose tissue. It will be discussed in the ensuing paragraphs how ectopic adiposity accounts for all metabolic consequences of obesity. It will be evident how 'adaptive' functions designed by nature for maintenance of good health turn 'maladaptive' when exposed to the challenge of energy excess. With this new understanding, 'ectopic fat' can be the 'new target' of obesity management.
| Understanding Fat Storage|| |
Normal fat storage - an adaptive mechanism for energy supply during fasting
Adipose tissue is the only dedicated storehouse of fat in our body. It stores excess calories as triglycerides (TG) in adipocytes. From an evolutionary perspective, this is the most efficient form of energy conservation, where stored triglyceride is released during periods of fasting or calorie deprivation. The major fat depots in the body are the subcutaneous adipocytes. Subcutaneous adipose tissue (SAT),  accounts for 80% of the total body fat.  Another 10% is stored in the body cavities as visceral adipose tissue (VAT), as omental, mesenteric and retroperitoneal fat. Remaining 10% fat is distributed at non-adipose tissues, such as skeletal muscles, nervous system, liver, pancreas, heart, blood vessels and bone-marrow, whereas very small amount of lipids are required for their structural support, normal cellular functions, membrane integrity and fluidity, neural signal transmission, thermo-regulation and cushioning of the organs. These sites are never designed for fat storage. Therefore, they have no capacity to store excess fat without causing harm.
Ectopic fat storage - maladaptation to calorie excess
Ectopic fat may be defined as the accumulation of TG in non-adipose lean tissues having no capacity for fat storage, resulting in organelle, cellular and organ dysfunction. The major sites of ectopic fat storage are skeletal muscles, liver, pancreas, heart, blood vessels and other visceral areas. Ectopic fat may be present in different organs simultaneously, giving rise to widespread metabolic consequences.
| Adipocytes Homeostasis|| |
Adipocytes are derivatives of mesenchymal stem cells
Adipocytes are derived from mesenchymal stem cells, which can differentiate to chondrocytes, osteoblasts, macrophages and adipocytes depending on the environment and transcription factors. Transcription factors such as peroxisome proliferator-activated γ (PPAR-γ), signal transducer and activator of transcription 5, CCAT/enhancer-binding protein alpha (C/EBP-α), cAMP response element-binding protein (CREB) promote differentiation of pre-adipocytes to adipocytes.  Numerous hormones, cytokines and growth factors regulate this differentiation.
Adipocyte hypertrophy, hyperplasia and ectopic fat
Adipose tissue is a dynamic organ which can enlarge throughout life, both by hypertrophy (increase in cell size) and by hyperplasia (increase in cell numbers). Challenged with calorie excess, adipocytes initially increase in size to store more energy in the form of TG. After the adipocytes reach a critical volume of 0.8-1.0 ml by hypertrophy,  the adipose tissue enlarge by hyperplasia, increasing the number of adipocytes to store more fat. There is heterogeneity in the capacity of adipocyte hyperplasia among individuals which may be determined by genetic, epigenetic and environmental factors.
In individuals with decreased capacity of adipocyte hyperplasia, excess energy is stored by further enlarging the size of the already enlarged adipocytes. So, a large fat cell is actually a marker of poor multiplicative potential of adipocytes. When the adipose tissue capacity to store excess fat by hypertrophy and hyperplasia of the adipocytes is overwhelmed, there is 'spillover' of this excess fat to other non-adipose ectopic sites, like skeletal muscles, liver, pancreas, heart and blood vessels, resulting in metabolic insults and multi-organ dysfunction.
| Adiposopathy or Sick Fat|| |
'Adiposopathy' or 'sick' adipose tissue depends on two factors - 'WHERE' the fat is stored and 'HOW' the fat is stored. Ectopic fat and large adipocytes are the two markers of 'adiposopathy' and are the most important determinants of the metabolic consequences of obesity, rather than the simple 'adiposity'. So, obesity is actually the excess and ectopic 'sick' adiposity.
| Adipocytes and Inflammation|| |
Large adipocytes are inflammatory
Increased fat cell size has been found to be the strongest marker of insulin resistance,  strongly correlating with the development of diabetes. A large adipocyte is a 'sick adipocyte'. Because it grows excessively in size outgrowing its own blood supply, resulting in hypoxia. The proliferating adipose tissue capillaries cannot keep pace with the rapidly expanding adipose tissue volume. Larger adipocytes reaching volumes of 1 ml are most susceptible to hypoxia, because the capillaries become unable to perfuse such an extent. Adipocyte hypoxia results in endoplasmic reticulum stress.
Endoplasmic reticulum stress is the starting point of cellular and organ dysfunction. It results in mitochondrial dysfunction, loss of membrane homeostasis, inflammation with release of pro-inflammatory cytokines and chemo-attractants, recruitment of macrophages resulting in a vicious cycle of more inflammation, finally culminating in insulin resistance. Insulin resistance has protean effects. The main highlights are insulin resistance in adipose tissue and skeletal muscles. Adipose tissue insulin resistance causes impairment of the anti-lipolytic effect of insulin, resulting in increased breakdown of adipose store and release of free fatty acids (FFA). FFA causes insulin resistance in the liver, skeletal muscles and other organs.
Hence large adipocytes are associated with increased cardio-metabolic risk, whereas small adipocytes do not pose such risks. In fact, smaller adipocytes are lipid hungry, highly insulin sensitive and maybe helpful in decreasing the metabolic consequences of obesity.
Ectopic fat in lipodystrophy and obesity is metabolically sick
Lipodystrophies, which are congenital or acquired syndromes characterized by loss of SAT mass, are characterised by severe insulin resistance. Inadequate SAT leads to storage of excess calories as triglyceride in ectopic sites such as skeletal muscles, liver and insulin-secreting pancreatic beta cells, resulting in severe insulin resistance, diabetes mellitus and other metabolic insults.
Same thing happens in obesity. The only difference is, in lipodystrophy, lipids accumulate in ectopic sites as the SAT mass is deficient, whereas in obesity SAT mass is adequate or increased. However, the capacity of this SAT mass to store fat is overwhelmed and overflown in obesity, resulting in spillover of excess lipid to ectopic sites, such as skeletal muscles, liver, pancreas, heart and blood vessels.
| Determinants of Ectopic Fat Accumulation|| |
Genetic, epigenetic mechanisms and environmental factors determine an individual's susceptibility to ectopic fat accumulation.
Genetic makeup of certain individuals or races is programmed for metabolic economy, favouring fat storage. Polymorphisms in the β-adrenergic receptors differ among individuals resulting in increased lipolysis and oxidation (catabolism) in some individuals, while increased lipid storage (anabolism) in others.  Other genetic differences, like perlipin expression, may favour fat accumulation in some individuals compared with others, for a similar amount of calorie excess.  Excess fat thus accumulated spills over to ectopic sites when it exceeds the storage capacity of SAT.
Genetic-epigenetic interface and low SAT capacity
In the late 20 th century there existed a concept that preventing adipocyte differentiation could be a treatment for obesity. This was rebutted by Danforth who said 'Preventing adipocyte differentiation would exchange obesity for diabetes'.
The SAT acts as a 'sink' to store the excess fat, with larger capacity preventing spillover at ectopic sites. PPAR-γ agonists increase the SAT mass by both hyperplasia and hypertrophy, resulting in increased 'sink' capacity, thus decreasing spillover to visceral and ectopic sites. This is the reason why they improve insulin resistance despite weight gain.
SAT volume is determined to a large extent by genetic makeup and by epigenetic factors (genetic expression). Epigenetic mechanisms in intrauterine life can influence expression of developmental genes designed for SAT and VAT. As a result, some individuals may have lower SAT volume for the same amount of adiposity, leading to easy spillover of fat at ectopic sites. G protein-coupled receptor 120 lipid receptor polymorphism is associated with a reduced capacity to proliferate SAT, resulting in ectopic storage of fat in liver and muscles. 
South Asian babies have lower muscle mass, higher fat mass and lower SAT volume for the same body weight compared to Caucasians.  This is determined by both genetic and epigenetic factors and is the 'mystery' behind the thin fat Indians. The metformin in gestational diabetes: The offspring follow-up study found higher SAT mass in children of mothers who were given metformin during pregnancy and this may prove to be protective against the future risk of obesity related complications. 
Maternal nutrition - a major epigenetic determinant of future obesity
Epigenetic events play a vital role in facilitating well-being and survival of the foetus in adverse environments like maternal malnutrition. When faced with maternal undernutrition, it allows expression of genes important for foetal survival and decreases expression of genes having lesser importance for survival. Thus a 'thrifty phenotype' is developed in the offspring of malnourished mothers.  This phenotype favours the development of important organs like brain, at the cost of poor development of other organs such as adipose tissue, skeletal muscles, kidney, liver and pancreas. Adaptations made in the intra-uterine life assume that the same nutritional environment will prevail throughout life. When exposed to increased calorie in later life, these adaptations turn maladaptive with the accumulation of excess fat at visceral and ectopic sites.
| Consequences of Excess Fat|| |
Increased adipose tissue mass causes harm by three mechanisms:
- Metabolic: By impaired cellular and organ functions induced by ectopic fat storage, leading to hyperglycaemia, dyslipidaemia etc.
- Inflammatory: By adipo-cytokines and growth factors induced by adipocyte hypoxia, e.g., Tumour necrosis factor alpha (TNF-α), interleukin (IL-6), Resistin etc., leading to accelerated atherosclerosis.
- Mechanical: By altered bio-mechanics, leading to osteo-arthitis, low back pain, sleep apnoea etc.
- Harm mediated by first two mechanisms is caused by ectopic fat and/or sick fat.
| Ectopic Fat and Multi-organ Metabolic Dysfunction|| |
Most of the metabolic consequences of obesity will not develop in the absence of ectopic fat deposition. Quantitative excess of lipids at ectopic sites causes harm, but qualitative change in lipid components may cause greater harm. Intermediaries of lipid metabolism such as ceramides, diacylglycerol (DAG), reactive oxygen species and reactive nitrogen species cause more inflammation, mitochondrial dysfunction, endoplasmic reticulum stress and insulin resistance, rather than mere TG. Therefore, qualitative lipodomics and modifying the fat type, not just fat content, may be the new focus of obesity treatment in the future.
Ectopic fat in skeletal muscles
Accumulation of TG in the intra-myocellular and inter-myocellular sites leads to lipotoxicity, insulin resistance and impaired glucose metabolism. , Increased intra-myocellular lipid (IMCL) content is a strong predictor of insulin resistance and is associated with decreased mitochondrial oxidation and phosphorylation. 
In obesity and in type 2 diabetes mellitus, skeletal muscle insulin resistance is due to a post-receptor defect. Normally, FFA that enters the muscles gets converted to long chain fatty acyl coA (LCFA-coA), which undergoes β-oxidation after being transported into the mitochondria by carnitine palmitoyl transferase. If LCFA-coAs are not oxidized, they are re-esterified to DAG, triacylglycerol or TG. When levels of FFA are high as seen in insulin resistance, oxidation of fatty acids is overwhelmed resulting in increased accumulation of fatty acid intermediaries like ceramides and DAG. These intermediaries impair the insulin signalling by activating serine/threonine kinases.  Serine/threonine kinases phosphorylate insulin receptor substrate-1, inhibiting its ability to propagate downstream insulin signalling, resulting in a post receptor defect and insulin resistance. This ultimately leads to decreased GLUT-4 transport, defective oxidative (glycolysis) and non-oxidative (glycogenesis) glucose metabolism and increased glycogenolysis.
Ectopic fat in the liver
Non-alcoholic fatty liver disease (NAFLD) is a condition where liver fat is >5%, in the absence of excess alcohol use (>20 g/day in females and >30 g/day in males) and in the absence of viral or autoimmune disease and toxins. Obesity is strongly associated with NAFLD. Ectopic fat accumulation in the liver is both the cause and effect of insulin resistance.
Liver fat can be derived from (i) adipose tissue lipolysis, (ii) dietary chylomicrons and (iii) de novo lipogenesis in the liver. Normally the major source of liver fat is dietary chylomicrons. But in patients with visceral adiposity most of the liver fat is derived from adipose tissue lipolysis. Insulin resistance in obese patients caused by adipose tissue hypoxia and inflammation results in more lipolysis (due to loss of anti-lipolytic action of insulin), release of more FFA which enters the liver and gets re-esterified to TG. Insulin resistance in skeletal muscles impairs glycogen storage in them, leading to increased hepatic lipogenesis. The resulting hepatic steatosis causes hepatic insulin resistance, which leads to important metabolic and atherogenic complications, such as fasting hyperglycaemia, loss of post-prandial suppression of gluconeogenesis and dyslipidaemia. At the same time loss of insulin's direct inhibitory action on very low density lipoprotein (VLDL) production in the liver due to hepatic insulin resistance, results in raised TG, low high-density lipoprotein and small dense low density lipoprotein (LDL). Steatosis induced liver dysfunction also leads to increased release of pro-atherogenic and pro-coagulant proteins like fibrinogen, PAI-1 and CRP. Combination of all these factors increases the risk of atherosclerotic cardiovascular disease (CVD).
NAFLD is a well-recognised risk factor for CVD. Degree of endothelial dysfunction and carotid intima media thickness (CIMT) strongly correlate with the severity of NAFLD. Current evidence strongly suggests that fatty liver is not only a marker but also an early mediator of atherosclerosis. 
Increased liver fat ultimately leads to cirrhosis of liver. NAFLD is an important cause of end stage liver disease and will become the leading cause of liver transplantation by 2020.
Ectopic fat in the pancreas
Ectopic fat deposition in and around the pancreas has been linked to development of diabetes.  In obesity increased fat in the pancreas comes from increased lipolysis in visceral fat and increased hepatic output of triglyceride rich particles. This ectopic fat causes lipotoxicity and accelerates the onset of diabetes by causing β-cell dysfunction in individuals who are already insulin resistant.
Ectopic fat in the kidney
Ectopic fat accumulation in the kidney especially around the renal sinus causes hypertension and chronic renal disease. Fatty kidney is frequently seen in conjunction with abdominal obesity. Hypertensive patients with systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg have higher levels of renal sinus fat. 
Renal sinus fat increases the renal interstitial pressure by compressing the renal vein and lymph vessels leaving the kidney. Smaller increase in renal interstitial pressure opposes tubular reabsorption, while larger increase compresses the tubules and medullary vasa recta. This reduces the tubular flow in loop of Henle, decreases the medullary blood flow and results in decreased NaCl delivery to the macula densa and increased sodium and water reabsorption, contributing to increased glomerular filtration rate and renin secretion in obesity. Accumulation of fat in the renal parenchyma also causes hypertension and renal damage by inflammation, lipotoxicity and fibrosis.
Ectopic fat in the heart
Epicardial and intra-myocardial accumulation of fat affects the heart both mechanically and functionally. It increases the stiffness of the cardiac muscles resulting in decreased cardiac contractility,  diastolic dysfunction  and cardiomyopathy, in addition to cardiac lipotoxicity, impaired glucose and fatty acid metabolism. , Intramyocellular accumulation of fat releases inflammatory cytokines, attracts macrophages and creates an inflammatory milieu and insulin resistance.
Epicardial fat is the visceral fat of the heart, present between myocardium and visceral pericardium. There is no structural separation between it and the myocardium, and both share a common blood supply. A small amount of epicardial fat is required normally for thermo-protection and cushioning of the heart, whereas in obesity excess amount is deposited in this ectopic location. Myocardium utilises FFA as the main source (50-70%) of its energy requirement. Normally epicardial fat is the major source of FFA supply to the heart, acts as an energy buffer and it has more capacity to release FFA compared to SAT. 
Increased epicardial fat mass is highly inflammatory, has a large amount of macrophages and it releases inflammatory and atherosclerotic cytokines, which gain direct access to the heart and circulation by both vasocrine and paracrine effects. Epicardial fat depot is most implicated in the pathogenesis of coronary artery disease (CAD) due to its close anatomic contact with the coronary arteries, , and has a strong positive correlation with the presence of coronary atherosclerosis. , In the framingham heart study, the prevalence of CAD and myocardial infarction correlated strongly with epicardial fat accumulation.  Increased epicardial fat has a positive correlation with increased intrabdominal fat and increased CIMT. 
Hence, epicardial fat is a marker of ectopic fat, indicative of a very strong cardiovascular risk.
Ectopic fat in blood vessels
Perivascular ectopic fat deposition affects the vasculature both mechanically and functionally. It modulates vascular tone, increases its stiffness, induces hypoxia, oxidative stress, and causes adventitial inflammation, which causes vascular smooth muscle proliferation and accelerated atherosclerosis. Strong association has been seen between central obesity and peripheral arterial disease. 
Ectopic fat and polycystic ovary syndrome (PCOS)
There is increasing evidence of an association between PCOS and ectopic fat. Steroidogenic regulatory factor FOS gene is under-expressed in adipose tissue of individuals with PCOS and is genetically associated with increased susceptibility to PCOS.  Absence of white fat, insulin resistance and increased ectopic fat are noted in transgenic mice with ablation of activator protein-1 (AP-1) function. AP-1 activity is necessary for adipose tissue development. AP-1 transcription factor FOS (FBJ murine osteosarcoma viral oncogene homologue) plays an important role in the pathogenesis of PCOS. FOS has functions in reproductive and metabolic pathways. Under-expression of FOS gene increases androgen production in ovarian tissues and promote insulin resistance in adipose tissue of PCOS patients.
| Visceral Fat and Cardio-Metabolic Risk|| |
VAT normally represents only 10% of total body fat in health. VAT has more active lipolysis and is more inflammatory than SAT. It breaks down to FFA easily and releases directly into the portal vein, gaining direct access to the liver. , A direct relationship between VAT size and FFA release into the liver is seen.  Hepatic overload of FFA causes fatty liver, hepatic insulin resistance, , increased hepatic gluconeogenesis, fasting hyperglycaemia, increased VLDL production and dyslipidaemia. Increased VAT is associated with higher risk of atherosclerotic cardiovascular disease.
Increased VAT out of proportion to the body weight actually reflects the decreased 'storage' capacity of SAT, and decreased potential of adipocytes to grow in numbers ('hyperplasia'), leading to enlargement in size of adipocytes ('hypertrophy'). Large adipocytes release pro-inflammatory cytokines like TNFα, IL-6, resistin and decrease the release of beneficial adiponectin. A vicious cycle of inflammation, macrophage infiltration and insulin resistance goes on and on.
| Metabolic Flexibility|| |
Skeletal muscles utilise 'FFA' as fuel during fasting state and efficiently to utilization of 'glucose' as fuel during insulin stimulated fed state. This 'switch over' is known as metabolic flexibility.  A tight regulation between lipolytic and anti-lipolytic activity in adipose tissue is required to shift this substrate utilisation from fasting to hyperinsulinemic fed state. This 'metabolic switch' is regulated by insulin.
Ectopic fat hampers metabolic flexibility
Insulin resistance results in increased FFA level despite hyperinsulinemia, leading to metabolic inflexibility. Ectopic fat causes insulin resistance and thus hampers metabolic flexibility.
Physical inactivity causes metabolic inflexibility
Physical inactivity is the major cause of ectopic fat accumulation and metabolic inflexibility. Decreased muscles workload leads to remodelling of muscles, reduced mitochondrial oxidative capacity, decreased β-oxidation of FFA and metabolic inflexibility. Physical inactivity leads to poor fat oxidation, accumulation of intermediaries of lipid metabolism like ceramides and DAG in the muscles, resulting in skeletal muscle insulin resistance. In the face of hyperinsulinemia due to insulin resistance, there is even lesser oxidation of FFA, resulting in its spillover to ectopic sites like the liver, skeletal muscles, blood vessels and other major organs.
Exercise decreases excess fat accumulation at visceral and ectopic sites, thereby increasing insulin sensitivity. It translocates GLUT4 transporters to the cell surface, increases peripheral uptake of glucose,  activates the 'metabolic master switch' AMP-activated protein kinase and increases insulin signal transduction. , All these effects are seen independent of weight loss.
| Fructose-Accelerator of Obesity Epidemic|| |
Widespread use of synthetic fructose in almost all kinds of modern foods and soft drinks has inexorably increased the burden of ectopic fat across the globe in recent years. Meteoric rise in fructose consumption worldwide has been linked with an epidemic increase in obesity, fatty liver, diabetes and metabolic syndrome in last three decades. Fructose metabolism is insulin independent. It does not increase the release of insulin or leptin, nor does it suppress the hunger hormone ghrelin. So it does not induce satiety, resulting in increased consumption. It is rapidly extracted by the liver and causes 100% de novo lipogenesis in the liver, leading to fatty liver, hepatic insulin resistance, hypertriglyceridemia, hyperuricemia, hypertension and oxidative stress. It parallels to alcohol in every aspect in producing fatty liver. Moreover, fructose destroys the gap junctions 'occludins' in small intestine, leading to increased lipopolysaccharide absorption,  which causes more inflammation and insulin resistance.
| Trans Fat-Accelerator of Ectopic Fat|| |
Trans-fat is a synthetic vegetable fat widely used in almost all fast foods and snacks throughout the world. It contributes significantly to the four modern epidemics of non-communicable diseases-obesity, diabetes, ischaemic heart disease and cancers. Whatever amount of trans-fat is ingested, it accumulates throughout our life at various ectopic sites because once deposited our metabolic system does not have the machinery to metabolise it. Moreover trans-fat promotes the growth of harmful gut microbiota like Firmicutes at the expense favourable bacteria like Bacteriodetes.  Strong links between gut microbiota and obesity are already known.
| Ectopic Fat-the New Target for Obesity Treatment|| |
Thus the main target of obesity management should be to decrease the ectopic and visceral fat. This should be brought about by calorie restricted diet, increased physical activity and development of drugs that have the potential to increase the number of subcutaneous adipocytes and to decrease the ectopic and visceral fat. Furthermore, the drugs that affect the lipid type at ectopic sites are an interesting option.
The good news - ectopic fat is more responsive to treatment
Ectopic and visceral fat are very responsive to weight loss. Weight loss of around 10% of the initial body weight in an abdominally obese person can reduce visceral fat by almost 30%.  As much as 50% of liver fat can be mobilised with 10% of weight loss.  Liver fat concentration can be best quantified non-invasively by proton magnetic resonance spectroscopy and it can detect small changes in fat content. Hypocaloric, fat-restricted diet causing 8% weight loss is associated with reduction in liver fat by 40-80%.  Treatment with thiazolidinediones can reduce liver fat by 30-50% and thus modulates insulin sensitivity in type 2 diabetes. 
Mere 5-10% weight loss imparts significant benefit in cardio-metabolic risk reduction. This is true because, even this minor loss in body weight is associated with a substantial reduction of visceral and hepatic fat to the tune of 40-50%. This fact highlights the role of ectopic fat in the genesis of harmful consequences of obesity.
| Conclusion|| |
Fat accumulation at ectopic sites is the most important cause of almost all the metabolic consequences of obesity. Certain individuals and population groups, like South Asians, are highly susceptible to ectopic fat deposition due to the genetic, epigenetic factors and maternal nutritional status.
Every cardio-metabolic effect of obesity can be explained by ectopic fat. Hyperglycaemia, due to the combined effect of increased hepatic glucose output, decreased glucose utilization by skeletal muscles and increased dysfunction of pancreatic β cells, is the result of ectopic fat accumulation in the liver, skeletal muscles and pancreas. Dyslipidaemia is the product of hepatic steatosis. Hypertension can be explained by the effects of hyperinsulinemia arising out of insulin resistance and by the ectopic fat in the renal sinus, renal parenchyma and blood vessels. Ectopic fat in the heart accounts for cardiac dysfunction resulting in heart failure. It can cause coronary atherosclerosis via release of inflammatory cytokines from epicardial fat with paracrine and vasocrine effects. Hepatic dysfunction and adipose inflammation create a pro-coagulant environment. There is a strong association between PCOS and ectopic fat deposition, which may be genetically determined. Fructose and trans-fat consumption contribute to this epidemic by causing inflammation, insulin resistance and changes in the gut microbiota.
Treatment should aim at negative energy balance by lifestyle changes. Drugs that increase the SAT and adipocyte numbers will be helpful. Physical activity plays the most important role in decreasing ectopic fat with or without weight loss, because it improves metabolic flexibility and increases insulin sensitivity independent of weight change. Improving maternal nutrition will play a significant role in the primordial prevention of ectopic fat and its consequences.
| Summary|| |
There has been a paradigm shift in our understanding of the pathophysiology of the metabolic complications of obesity. Obesity is not merely an increase in body weight. Many muscular athletes have high body weight, yet they are healthy. It is actually the increased body fat content or increased adiposity, which is the harmful component of increased body weight. However, all people with increased adiposity may not have the same harmful metabolic consequences of obesity. That is why conditions like metabolically-normal obese and MONW are recognised.
This kind of metabolic discrepancies in individuals with the same amount of adiposity depends on the differences in their location of fat storage. SAT is the only dedicated fat store in our body and accounts for 80% of the total adipose tissue in healthy subjects. VAT normally accounts for 10%. Cell membranes and cellular components of other lean tissues normally require and contain rest 10% of the body fat for their structural support and functional health. However these tissues are not actually meant for fat storage and do not have any capacity for this. Deposition of any excess fat in these non-adipose tissues, like the skeletal muscles, liver, pancreas, kidneys, heart, blood vessels and even ovaries is designated as ectopic fat. It has now become obvious that this ectopic fat is the most important factor behind and is responsible for almost all metabolic consequences of obesity.
- SAT acts as the 'sink' to store excess fat in our body when faced with positive energy balance. Increased SAT mass is not that detrimental. When the SAT volume is inadequate, fat easily spills over to visceral area and various ectopic sites. Larger the capacity of SAT, lower is the spill over to the ectopic sites.
- Size of the adipocyte is also very important. Whenever the adipocytes are exposed to excess energy, they accommodate it by enlarging their size (hypertrophy), and by increasing their number (hyperplasia). When adipocytes in SAT fail to increase in number in response to sustained calorie excess, they just enlarge in size. These hypertrophied or large adipocytes are prone to hypoxia due to poor perfusion from capillaries, resulting in a release of various inflammatory adipocytokines. A large adipocyte is always a 'sick' adipocyte and is a strong marker of insulin resistance.
- 'Adiposopathy' or 'sick' adipose tissue depends on two factors: 'WHERE' the fat is stored and 'HOW' the fat is stored. Ectopic fat and large adipocytes are the two markers of 'adiposopathy' and are the most important determinants of the metabolic consequences of obesity, rather than the simple 'adiposity'. Hence, obesity is actually the excess and ectopic 'sick' adiposity.
- Accumulation of fat in non-adipose ectopic sites is the most important predictor of morbid complications of obesity, such as diabetes, hypertension, dyslipidaemia, fatty liver, CAD etc., Ectopic fat storage carries more cardio-metabolic risk than general fat accumulation. Every adverse metabolic effect of obesity can be explained by ectopic fat.
- Hyperglycaemia - the combined effect of increased hepatic glucose output, decreased glucose utilisation by skeletal muscles and increased dysfunction of pancreatic β cells, is the result of ectopic fat accumulation in the liver, skeletal muscles and pancreas respectively. Related hyperinsulinemia has been linked with increased incidence of various cancers.
- Hypertension is the effect of both hyperinsulinemia due to insulin resistance and ectopic fat in the renal sinus, renal parenchyma and blood vessels. Ectopic fat in and around the heart accounts for cardiac dysfunction leading to heart failure and may cause coronary atherosclerosis via release of inflammatory cytokines from epicardial fat.
- Dyslipidaemia is the product of hepatic steatosis. Hepatic dysfunction and adipose tissue inflammation create a pro-coagulant environment. These two factors ominously contribute to various ischaemic events.
- Targeting ectopic fat has become the real target in obesity management. The good news is that ectopic and visceral fat are very responsive to weight loss. Mere 5-10% weight loss is associated with a substantial 40-50% reduction of visceral and hepatic fat, imparting significant benefit in cardio-metabolic risk reduction.
- Meteoric rise in consumption of fructose and trans fat with almost all kinds of modern food, snacks and soft drink, and excessive intake of energy-dense food is responsible for the world-wide epidemic increase in obesity, fatty liver, diabetes, dyslipidaemia and metabolic syndrome in last three decades, as a result of excess ectopic fat.
- South Asians are more vulnerable to ectopic fat deposition compared to the Caucasians with similar body weight and adiposity, due to their genetic and phenotypic characteristics, marked by poor muscle mass and low SAT volume. Due to their poor muscle mass they have more adiposity with similar body weight and equal energy intake. And due to their low SAT volume this excess fat easily spills over to the ectopic sites, with resultant metabolic consequences. Hence, mindlessly aping the modern western life-style will cause more harm to us than they do to other less susceptible population.
- Maternal malnutrition is an important contributor to ectopic fat. It decreases the muscle mass and SAT capacity as a result of the 'thrifty phenotype' and thus increases the risk of ectopic fat and the future risk of related diseases in the offspring. Targeting maternal malnutrition is thus a primordial means of prevention of ectopic fat accumulation.
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