Weight Loss

What makes abdominal fat so lethal? What system in the body ‘encourages’ fat deposits in the abdominal area?

WE are bombarded with an almost unlimited variety and availability of food. Just take a look at how many 24-hour eateries there are around you. You can practically find food anytime of the day in most parts of Malaysia.

For those of us who partake, this increase in energy intake coupled with a sedentary lifestyle leads to a state of energy imbalance. This imbalance leads to increased fat accumulation and higher cardiometabolic risks (see What’s your risk?, Fit 4 Life, Feb 17), resulting in life-threatening consequences such as type 2 diabetes and cardiovascular diseases.

Despite advances in treatment, cardiovascular disease (CVD) remains the leading cause of death worldwide, causing an estimated 17 million deaths each year (49% of all deaths in Europe and 39% in the US), according to the World Health Organisation.

In Malaysia, 29.9% of deaths in 2002 are due to cardiovascular diseases.

Current treatment strategies for cardiovascular disease generally target individual cardiometabolic risk factors, and although they have successfully contributed to reduced mortality and morbidity, there is still a significant residual risk.

Treatment strategy to reduce cardiometabolic risk . . . In the central nervous system, the cannabinoid receptors (CBI receptors) of the Endocannabinois System are necessary to kick-start food intake after a short period of food deprivation, and when activated, they also preferentially stimulate the appetite. Therefore an overactive endocannabinoid system in the brain can lead to an increase appetite and food intake: which will lead to increase in body weight and fat accumulation.
The question is, can we achieve further improvement by addressing the underlying causes of type 2 diabetes and CVD? Not all body fat is alike. In recent years, it has become apparent that among overweight and obese people, i.e. those with abdominal obesity, are at the greatest risk of developing metabolic disorders such as type 2 diabetes and dyslipidaemia (abnormal lipids) or cardiovascular diseases such as coronary heart disease and stroke.

Abdominal obesity, which is simply measured by waist circumference, is associated with the presence of excess intra-abdominal adiposity.

Associated risks

Many studies have shown that overweight and obese individuals tend to be at higher risk of hypertension, dyslipidaemia and cardiovascular diseases.

However, weight gain is not the only factor in this equation. In recent years, it has become increasingly clear that the distribution of fat is important when considering the risks of obesity.

It was first suggested in 1947 by the French physician, Jean Vague, that cardiovascular and metabolic risk is more closely related to “android” obesity (abdominal obesity or “apple-shaped”) than to “gynoid” obesity (lower body obesity or “pear-shaped”).

In recent years, new data has emerged regarding the link between cardiovascular risk and abdominal obesity, specifically the significance of intra-abdominal adiposity (fat stored in the intra-abdominal cavity around the major organs), as an important risk factor for cardiovascular disease.

It has also become apparent that adipose tissue (fat cells) can be regarded as an endocrine organ directly contributing to cardiovascular risk by secreting a number of molecules known to have an effect on vascular, metabolic, inflammatory and other functional aspects of the cardiovascular system.

The recent INTERHEART study, which assessed the relationship between a variety of risk factors associated with heart attacks in 52 countries (Malaysia is part of the study), found that abdominal obesity was an independent risk factor for heart attack and a better predictor of heart attack than BMI.

In this context, BMI is still useful but waist circumference can further delineate the risk on of individual.

The Malaysian NCD (non-communicable disease) surveillance (a survey done by the Health Ministry in 2005/2006) revealed an alarming rate of abdominal obesity among Malaysians. The prevalence of abdominal obesity was 48.6%. About 40.7% of men and 57.1% of women were assessed to have abdominal obesity.

The survey estimated that about 5.8 million or one in two adults aged 25-64 years were found to have abdominal obesity.

The recent discovery of the Endocannbinoid System (ECS) has accelerated research to uncover their physiological roles in regulating body weight, glucose and lipid metabolism.
Excess intra-abdominal adiposity (IAA) and metabolic disorders

Abdominal obesity (which can be simply measured by waist circumference) is associated with an increased risk of developing metabolic disorders and cardiovascular disease. It is intra-abdominal fat, located deep in the abdominal region and around the major organs of the body, which is thought to be associated with cardiometabolic disorders such as dyslipidaemia, insulin resistance, type 2 diabetes, metabolic syndrome, inflammation and thrombosis.

This intra-abdominal fat contains cells called adipocytes, whose primary function is to store and release energy. In essence, when the body is in a fasting state, the adipocytes break down triglycerides to make energy available for use by the body (lipolysis).

When the body is in a post-prandial state (after eating), the balance shifts to promote lipogenesis, the process of storing excess fuel as triglycerides.

Insulin plays a key role in regulating the process of energy storage and release. Increased circulating levels of insulin in the bloodstream after a meal cause adipocytes to form and store triglycerides.

Insulin also plays a role in the breakdown and use of stored triglycerides as energy by adipocytes. Type 2 diabetes and obesity are characterised by a large number of adipocytes that have become resistant to insulin, resulting in an excessive amount of fuel being stored by the adipocytes as triglycerides.

Endocannabinoid System: Its role in cardiometabolic risks

The recent discovery of the Endocannabinoid (EC) System, a physiological system of cannabinoid receptors and corresponding chemical messengers or endocannabinoids, has accelerated research to uncover their physiological roles in regulating body weight, glucose and lipid metabolism.

The modern history of cannabinoid pharmacology began in 1964, when tetrahydrocannabinol (THC) was isolated.

Tetrahydrocannabinol is an exogenous cannabinoid and the active component in marijuana. It is the compound responsible for the effects of marijuana.

The finding paved way to our understanding of the endocannabinoid system. In 1991, the first human cannabinoid receptor was cloned and this led to further interesting discoveries of the endocannabinoid system.

In general, the endocannabinoid system is involved in many different physiological functions, many of which relate to stress-recovery systems and to the maintenance of homeostatic balance.

Among other functions, the endocannabinoid system is involved in the modulation of pain, regulation of motor activity, and the control of certain phases of memory processing.

In addition, the endocannabinoid system is involved in modulating immune and inflammatory responses. It also influences the cardiovascular and respiratory systems.

The most extensively studied role of the endocannabinoid system is its role in regulat ing energy and fat metabolism.

The endocannabinoid system is a natural endogenous physiologic system believed to play an important role in cardiometabolic risk, in that increased activity in this system is thought to notably affect the accumulation of fat, especially intra-abdominal fat.

The endocannabinoid system, particularly in the brain, is thought to be “turned off” or relatively silent under normal conditions and believed to become activated under certain circumstances.

In the “on” mode, this system assists in enabling relaxation, reducing pain and anxiety, and initiating sedation or a slowing of metabolism. The system acts in different pathways, centrally and peripherally, to maintain a balance in our metabolic processes.

What is important is that through chronic transient activation, the endocannabinoid system appears to stimulate appetite, creating a metabolic imbalance and resulting in much pathology.

Recent published studies show that diabetics and obese human subjects show higher level of endocannabinoid activity (activity is switched “on”).

How can over-activity of the endocannabinoid system increase an individuals’ cardiometabolic risks?

Let us look closer at sites where endocannabinoid system is active. Currently we know that the endocannabinoid system has activity centrally; in the brain and peripherally; in the liver, fat cells (adipose tissues), skeletal muscle, gastrointestinal tract.

The cannabinoid receptors are found extensively in the brain, especially in the nucleus acumbens region, which is believed to be important in motivational processes that mediate the incentive value of food.

Studies indicate that endocannabinoid may play a very specific role in food intake.

In the central nervous system, CB1 receptors are necessary to kick-start food intake after a short period of food deprivation, and when activated, they also preferentially stimulate the appetite.

Therefore an overactive endocannabinoid system in the brain can lead to an increase appetite and food intake; which will lead to increase in body weight and fat accumulation.

At the peripheral level, the activation of the CB1 receptors have been shown to stimulate lipogenesis (lipid/fat formation) in adipocytes, which results in fat accumulation and modulation of the expression of adiponectin, a hormone that regulates the metabolism of lipids and glucose.

In the liver cells, stimulation of the cannabinoid system increases formation of fatty acids.

Another observation noted is that cannabinoids activity can lead to increase storage of fat in the hepatocytes, leading to hepatic steatosis and fatty liver.

Through a dual central and peripheral mechanism of action, the endocannabinoid system helps to regulate food intake, and ultimately energy storage and utilisation as well as fat accumulation. These conditions, in turn, create an increased cardiometabolic risk, which can lead to diabetes and cardiovascular diseases.

Physiologically, the endocannabinoid system is activated (switched “on”) in response to stressful stimuli to help re-establish the normal steady state of the affected cells or tissues.

Normally, the effects of the endocannabinoid system activation are short-lasting, confined to those cells or tissues that have been subjected to stress or damage, and normally end once the organism has recovered from a transient “unbalanced” condition.

Alas, the combination of a sedentary lifestyle and a calorie-dense diet, which is typical of our modern way of living, can disrupt the energy balance system, leading to obesity and chronic over-stimulation of the endocannabinoid system (permanently switched “on”).

Targeting the Endocannabinoid system

Although there are still gaps in our knowledge of this system, what we currently know is very encouraging; The endocannabinoid system is an endogenous and physiological system that plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism and its overactivity leads to pathological consequences of the modern society like obesity and increase cardiometabolic risks.

It is normally inactive (switched “off”) but is over-activated (permanently switched “on”) in the obese and diabetic subjects. The endocannabinoid system can be blocked both centrally and peripherally in the adipose tissue to help normalise an over-activated endocannabinoid system.

Targeting the endocannabinoid system represents a new and exciting approach for the reduction of cardiometabolic risks. Next week: Drug that targets the Endocannabinoid System