Epinephrine (E), often called adrenaline, is known as the quintessential stress hormone, released from the adrenal medulla in response to stresses like low blood sugar. While it's recognized for its role in increasing blood glucose levels, its impact on weight loss and metabolism is complex and multifaceted. Understanding the underlying mechanisms is crucial to unraveling the potential therapeutic applications and addressing common misconceptions.
Epinephrine's Acute Metabolic Effects
When administered, epinephrine increases blood glucose by inhibiting insulin release, stimulating glucagon release, and promoting hepatic glycogenolysis and gluconeogenesis in the liver and kidneys. This acute effect has led to the general perception that epinephrine raises blood glucose. However, this understanding is incomplete, as the long-term effects of endogenous epinephrine and its interaction with adrenergic receptors present a more nuanced picture.
The Paradox of Adrenergic Agonists and Antagonists
Paradoxically, while epinephrine, a β-adrenergic agonist, acutely increases glucose and decreases insulin sensitivity, β-adrenergic antagonists have also been associated with increased blood glucose and decreased insulin sensitivity. This highlights the complexity of the adrenergic system and the importance of distinguishing between acute and chronic effects, as well as the specific receptors involved.
Epinephrine Synthesis and Its Significance
Epinephrine is synthesized from norepinephrine (NE) by the enzyme phenylethanolamine N-methyltransferase (PNMT) and is a more potent β2-adrenergic agonist than NE. In addition to stimulating the release of metabolic substrates, epinephrine stimulates metabolic rate. Both epinephrine and NE stimulate β3 receptors to promote fat metabolism, although this is predominantly a response to neuronal NE release. However, physiological epinephrine levels also stimulate a thermogenic response in humans.
The Role of Epinephrine in Overfeeding-Induced Diabetes
Given that weight gain and stress are characteristics of industrialized societies, the stress hormone epinephrine might play a role in the current epidemic of type II diabetes. To investigate this, researchers created a PNMT knockout mouse, which cannot synthesize epinephrine, and backcrossed it into a mouse that develops type II diabetes in response to overfeeding.
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Experimental Setup
PNMT−/− cells were injected into C57BL/6 blastocysts and the chimeras were back crossed into C57BL/6 mice. Mice were housed at a constant temperature and on a 12-h light, 12-h dark cycle. All experimental procedures for the studies were approved by the Institutional Animal Care and Use Committee of the University of California San Diego.
In one experiment, 15 PNMT+/+ and 13 PNMT−/− male mice were fed a normal diet (14% kcal fat). Additionally, 10 PNMT+/+ and 10 PNMT−/− mice received a high-fat diet (40.6% kcal fat) for 10 weeks ad libitum. Animals were weighed bi-weekly and, at the end of 10 weeks, the intraperitoneal glucose tolerance test (ipGTT) and intraperitoneal insulin tolerance test (ipITT) were performed.
In another experiment to investigate the etiology of glucose differences and sex-specific effects, PNMT+/+ (9 males and 10 females) and 10 PNMT−/− (6 males and 4 females) mice were fed a high fat diet for 13 weeks. An additional 13 PNMT+/+ (7 males and 6 females) mice were given the β-adrenergic blocking drug propranolol (100-150 mg/kg) in their drinking water along with the high fat diet. Mice were weighed weekly and, at the end of 13-week high fat diet, underwent dual energy X-ray absorptiometry (DEXA) scan to determine their body composition.
Results and Observations
Knockout of the PNMT gene effectively blocked the production of epinephrine. When the PNMT−/− mice unable to synthesize E ate a normal diet, they had blood glucose levels slightly, but not significantly lower than PNMT+/+ mice. However, those on a high fat diet reversed this relationship leading to a significant diet by genotype interaction. The insulin sensitivity of PNMT+/+ and PNMT−/− animals on a 14% fat diet did not differ. The mice that ate a high fat diet were relatively insulin resistant and the PNMT−/− animals were the most insulin resistant.
The PNMT−/− mice weighed the same as PNMT+/+ animals when raised on a customary 14% fat diet and their glucose tolerance and insulin sensitivity did not differ. All of the mice used in this experiment were C57B/6 animals, which develop obesity and type II diabetes on a high fat diet. The PNMT−/− mice gained 20% to 33% more weight on a high fat diet, but their final body fat, muscle mass and total body weight did not significantly differ from control animals.
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Interpretation
The short-term effect of pharmacologic doses of epinephrine is to increase blood glucose and diminish insulin sensitivity. Surprisingly, normal epinephrine production had the opposite effect, protecting against diet-induced hyperglycemia and insulin resistance. There is reason to believe this is due to epinephrine stimulation of β2 receptors. PNMT−/− mice still had normal amounts of NE. Epinephrine stimulates β2 receptors better than NE, but has similar potency at α, β1 and β3 receptors.
Skeletal muscle is the most important site for glucose disposal and responds to β2 stimulation. A chronic epinephrine infusion enhanced rat muscle insulin sensitivity. Some β2-agonists in pharmacologic doses lead to muscle hypertrophy in rats cattle, pigs, poultry and sheep by decreasing breakdown of muscle protein. The short term effect of β2-agonist drugs is to increase insulin release. Six hours after administration of β2-stimulating drugs insulin sensitivity is diminished, but that effect is short lived.
Long-Term Effects of β2-Agonists and β-Blockers
While short-acting β2-agonists worsen glucose tolerance, chronic administration of long-acting β2-agonists improves insulin sensitivity. On the other hand, chronic use of β-blockers increases glycohemoglobin, decreases insulin sensitivity, and causes weight gain in humans. Thus, the long-term effect of chronic administration of β2-agonists is to increase muscle growth, blood flow, insulin binding, and insulin sensitivity.
This study indicates that the long-term effect of endogenous epinephrine is protection against the insulin insensitivity that accompanies a high-fat diet. Endogenous epinephrine also protects against exercise-induced blood pressure elevation and cardiac remodeling in mice on a normal fat diet.
Epinephrine, Aging, and Diabetes
Human overfeeding has become a worldwide phenomenon, as has type II diabetes. Adrenal epinephrine release and the epinephrine response to stress decreases with age, and deficient epinephrine responses are more common in diabetics. Although epinephrine is generally thought to raise blood glucose, this is an acute effect of pharmacologic doses.
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Fat Burners and Adipose Tissue
Adipose tissue, composed of adipocytes, is now recognized as a major endocrine organ. Fat loss occurs when fats are liberated from adipocytes into circulation to supply needed energy. Fat burners are nutrition supplements that increase fat metabolism, impair fat absorption, increase weight loss, and increase fat oxidation during exercise. A good fat burner must burn stored fats, break down fat cells, and increase the metabolic rate.
Types of Adipose Tissue: WAT vs. BAT
White adipose tissue (WAT) and brown adipose tissue (BAT) are the two main types of adipose tissues. WAT stores energy, while BAT generates body heat. The activity of BAT decreases with age and in obese individuals, making it a target for obesity and diabetes prevention.
Increasing Brown Fat Content
Increasing brown fat content has been explored as a strategy for weight management. Methods include chronic cold exposure and pharmaceuticals, but these can have side effects. A tissue-grafting strategy that converts white fat to brown fat outside the body and then re-implants it has shown promise.
The Process of Fat Burning and Fat Cells
When the body loses fat, the fat cell does not go anywhere or move into the muscle cell to be burned. The fat cell itself stays right where it was, but the fat is stored inside the fat cell in the form of triaglycerol. The fat is not burned right there in the fat cell; it must be liberated from the fat cell through somewhat complex hormonal/enzymatic pathways.
When stimulated to do so, the fat cell simply releases triaglycerol into the bloodstream as free fatty acids (FFA’s), and they are transported through the blood to the tissues where the energy is needed. By lipolysis, each molecule of triaglycerol splits into glycerol and three fatty acids. The reaction catalyzed by hormone-sensitive lipase (HSL). The stored fat gets released into the bloodstream as FFA’s and they are shuttled off to the muscles where the energy is needed.
As blood flow increases to the active muscles, more FFA’s are delivered to the muscles that need them. FFA’s get inside the mitochondria by LPL and this is where the FFA’s go to be burned. When the FFA’s are released from the fat cell, the latter shrinks and that is the reason for the leaner look when the body loses fat because the fat cell is now smaller. The scientists concluded that “we don't actually “lose” fat cells, we “empty out” fat cells".
The Impact of Stress on Weight
Stress, whether environmental or psychological, triggers a cascade of stress hormones, including epinephrine, that produce physiological changes. Over time, repeated activation of the stress response can take a toll on the body, contributing to high blood pressure, artery-clogging deposits, and brain changes that may contribute to anxiety, depression, and addiction.
The Fight-or-Flight Response
When someone experiences a stressful event, the amygdala sends a distress signal to the hypothalamus. The hypothalamus activates the sympathetic nervous system, leading to the release of epinephrine from the adrenal glands. This results in increased heart rate, blood pressure, and breathing rate, as well as the release of glucose and fats from storage.
Chronic Stress and the HPA Axis
Chronic low-level stress keeps the HPA axis activated, leading to persistent epinephrine surges that can damage blood vessels and arteries, increasing blood pressure and raising risk of heart attacks or strokes. Elevated cortisol levels also increase appetite, contributing to the buildup of fat tissue and weight gain.
Counteracting Stress
Counteracting the stress response can be achieved through relaxation techniques, physical activity, and social support.
Lifestyle Modifications and Weight Loss
Weight loss is an important preventative measure and is associated with a reduction in all-cause mortality. Weight loss associated with lifestyle modifications such as diet and regular exercise are important and remain the first-line treatment for obesity and obesity-related hypertension.
Diet, Exercise, and Blood Pressure
A combination of diet and exercise exerts a stronger ameliorative effect on weight loss, weight loss-induced blood pressure reduction, normalization of blood pressure, sympathetic activation, and insulin resistance compared with diet or exercise alone.
Neurohormonal Mechanisms
A calorie-restricted diet might lead to a normalization or suppression of the sympathetic overactivity associated with the blood pressure reduction accompanying weight loss and lead to an amelioration of insulin resistance. On the other hand, the exercise-only program might lead to a reduction in total fat mass with amelioration of HOMA-IR at 4 weeks and then significant reduction in plasma NE at 8 weeks. The significant blood pressure reduction occurred subsequently at 12 weeks.
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