"What makes abdominal fat so lethal? What system in the body ‘encourages’ fat deposits in the abdominal area?
By Dr BERNARD NG KEE HUAT"
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
This article is courtesy of sanofi-aventis.