Endotoxemia, Stress, and Metabolism
Although genetic and biological factors play a major role in the development of obesity, hypertension, insulin resistance, and diabetes, these common disorders that are part of the metabolic syndrome are probably influenced by other factors. Evidence suggests that these disorders are mediated by a complex interplay between genetics, biology, and the environment. Stress, whether related to depression, environmental stressors, or perceived stress, is associated with increased release of corticosteroids and other neurohormonal factors that may predispose to abdominal obesity, insulin resistance, and the other features of the metabolic syndrome.
Stress Response and the Metabolic Syndrome
I’m concluding my series on weight by examining the role chronic stress plays in energy metabolism. In my post on endotoxemia and weight regulation, I hinted how metabolic rate is adversely impacted by translocating gut pathogens so today I want to flesh out that idea.
This graphic should be familiar to those who read my post on endotoxemia and the hypothalamic-pituitary-adrenal axis (HPA) axis. I encourage you to read that entry if you haven’t already for a fuller explanation of what’s going on here.
The ability of translocating gut pathogens to stimulate this axis is central to understanding how elevations in glucococorticoids, like cortisol, will negatively impact basal metabolic rate. In response to gut pathogens breaching the gut wall, the immune system produces inflammatory cytokines and prostaglandins to stimulate the production of cortisol. What should be included in this graphic is tumor necrosis factor alpha (TNF-α); it too increases in response to endotoxemia. Elevated TNF-α is a common finding in the morbidly obese and those suffering from various health disorders.
Increases in cortisol, whether caused by endotoxemia or psychological stress, always compromises gut-barrier function, both in the small intestine and colon. Apart from a bad diet and taking certain drugs, I can’t think of a better way to develop disordered gut flora and a “leaky gut” than chronic stress. And once gut dysbiosis sets in, the chronic stress response this elicits will continually stimulate increased intestinal permeability and cortisol release in a feed-forward manner. Thyroid hormones and metabolic rate will also be impacted as I’ll explain in a minute. Before I do, let me briefly cover how the thyroid system works in a healthy human.
The hypothalamus is the primary regulator of metabolic rate and does so through the hypothalamic-pituitary-thyroid axis. The hypothalamus secretes thyrotropin-releasing hormone (TRH) in a pulsatile fashion throughout the day. TRH, in turn, signals the pituitary gland to release thyroid-stimulating hormone (TSH). TSH causes the thyroid gland to release two forms of hormone, thyroxine, known more commonly as T4, and triiodothyronine, known as T3. Of the two types, T3 is from three to four times more metabolically active than T4.
Both types of thyroid hormone require iodine derived from diet for their production. Therefore, not getting enough iodine from your diet can impair synthesis of these vital hormones as can malabsorption caused by small gut dysbiosis. The enzyme responsible for converting T4 to T3 requires selenium, so low levels of this element due to low dietary intake or malabsorption will also interfere with thyroid hormone synthesis. Other elements like bromine can interfere with this system, but I’ll forgo discussing this for now.
The thyroid produces anywhere from 70% to 80% of T4 and 20% to 30% of T3. As previously mentioned, a certain quantity of T4 is converted in various peripheral tissues and organs to the more metabolically active T3 in a process known as deiodination. Of the organs responsible for this conversion, the liver and kidneys rank first and second. Note that both these organs are also responsible for the majority of detoxification functions in the body, and would be most vulnerable to damage caused by translocating gram-negative bacteria and their cell-wall remnants, lipopolysaccharides (LPSs).
Thyroid hormone increases metabolic rate, secretion of growth hormone and catecholamines. The catecholamines include dopamine, norephinephrine, and adrenaline.
Now this is an admittedly simplified overview of thyroid hormone synthesis and function. For example, there are differences between the amount of free or bound thyroid hormone in blood serum, the production of transport proteins by the liver, the level of metabolically inactive reverse T3, the extent and health of various thyroid receptors throughout the body, and the rate thyroid hormone is degraded and excreted.
And a lot can go wrong with this system, including autoimmune disorders like Graves’ disease (overactive thyroid) or Hashimoto’s thyroiditis (underactive thyroid). Nevertheless, even when the hypothalamus, pituitary and thyroid gland are all working properly, chronic stress and LPSs will depress metabolic rate.
It is well documented that acute stress hormone release as in sepsis, can directly depress secretion of TSH from the pituitary gland and suppress downstream thyroid hormone release and conversion. (1) While chronic endotoxemia appears to spare direct damage to the hypothalamic-pituitary-thyroid axis, at least initially, it does lower metabolism by promoting euthyroid sick syndrome (ESS).
In this syndrome, levels of both TRH and TSH are normal, as are production of both T3 and T4 by the thyroid gland. In fact, clinical tests that fail to directly measure levels of serum T3 or reverse T3 will typically show no abnormalities in someone experiencing ESS.
The mechanism for metabolic derangement in euthyroid sick syndrome appears to be two-fold. First, translocating LPSs will directly down-regulate thyroid receptor activity. (2) All hormones require properly functioning receptors to affect biological processes. By interfering with receptor activity in the liver, lipopolysaccharides prevent these thyroid hormones from carrying out their functions even when their levels are in the normal range.
Secondly, stress hormones directly reduce the conversion of T4 to T3 in the liver, kidneys, and other peripheral organs. They do so because one of the functions of glucococorticoids is to shuttle energy to the brain and the heart in emergencies. Chronic stress, however, is a never-ending “emergency” that causes chronic stimulation of the HPA axis and cortisol release. (3)
Another cause of euthyroid sick syndrome is malnutrition brought about by starvation, fasting, or as I described here, malabsorption. If you are not properly digesting and absorbing nutrients from food because of small gut dysbiosis, your body is under stress, and stress will cause depression of metabolic rate. Add in endotoxemia and the stress response is further amplified.
Following are some common symptoms seen in those experiencing euthyroid sick syndrome:
- dry skin
- low basal metabolic rate
- heart rate under 60 beats per minute (bradycardia)
- hypothermia or feeling cold, especially in the extremities
- absence of menstrual periods in women of reproductive age (amenorrhoea)
- difficulty losing weight even with calorie restriction
- having low energy, feeling tired
Many people who battle weight issues are very familiar with this list of symptoms. It’s not uncommon, for example, for people experiencing endotoxemia- and/or malnutrition-induced euthyroid sick syndrome to have cold hands and feet. I’ve known many people who can’t tolerate sitting near or under a fan even on a hot day because they can’t tolerate any amount of cold. And many of these same people suffer from constipation and chronic fatigue. Someone who is constantly tired is not going to be too receptive to the idea of exercise.
While elevated cortisol levels cause a breakdown of tissue to fuel a rise in glucose production in the liver, it simultaneously depresses fat burning (lipolysis) by inhibiting the release of growth hormone from the pituitary gland. While acute endotoxemia can stimulate growth hormone release in the short-term, chronic endotoxemia arrests its secretion.
Growth hormone stimulates cell growth and regeneration in humans. It’s what is responsible for the rate of growth in children and young adults. Growth hormone is an anabolic agent whereas cortisol is a catabolic agent. It builds up your muscles while cortisol breaks them down. Some important functions of growth hormone apart from stimulating height in children include:
- increasing growth of muscle mass
- promoting breakdown of stored fat for use as fuel
- increasing bone density and buildup by retaining calcium
- increasing synthesis of protein
- stimulating growth of all internal organs except the brain
- stimulating the immune system
- maintaining the proper functioning of pancreatic cells responsible for blood glucose control
Chronic stress will inhibit all of this. Trying to lose weight and build muscle (not to mention bone) will be very difficult to do when chronic stress is inhibiting the secretion of growth hormone.
Stress hormones also reduce gonadotropins. Gonadotropins are hormones that regulate sexual development and reproductive function. The two principal types of gonadotropins are follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
In women, FSH and LH work together to start ovulation, making both hormones absolutely vital for reproductive function. In men, FSH is important for proper sperm formation and LH is responsible for the production of testosterone in the testes. As sex hormones also increase lipolysis and promote growth of muscle mass, inhibition of these biological agents will make fat loss harder to achieve.
In fact, increased weight gain is a common finding in those with Cushing’s syndrome. Cushing’s is caused by a tumor on the pituitary gland that causes increased release of adrenocorticotropic hormone (ACTH). This in turn increases the production of cortisol by the adrenals. Cushing’s patients typically have decreased lean body mass, increased visceral fat, osteoporosis, and depressed immune function.
To sum up, increased HPA axis stimulation is associated with:
- central obesity
- insulin resistance
- high-blood glucose
- decreased lean-muscle mass
- inability to breakdown stored fat for use as fuel
- allergic reactions
- migraines and headaches
- pain (abdominal, pelvic, low-back)
- cardiovascular disease
- osteopenia and osteoporosis
- protein breakdown
- immune system dysfunction
- pancreatic dysfunction
- severe chronic disease
- melancholic depression
- obsessive-compulsive disorder
- panic disorder
- excessive exercise (obligate athleticism)
- diabetes mellitus
- dry skin
- low basal metabolic rate
- daytime sleepiness
- heart rate under 60 beats per minute
- intolerance to cold
- absence of menstrual periods in women of reproductive age
- difficulty losing weight
- tiredness and fatigue
One last point. Appetite is either stimulated or inhibited by the stress response. One thing I left off this list is anorexia nervosa. It too has been associated with raised cortisol secretion via a stimulated HPA axis. While scientists are still investigating the precise mechanisms that influence how stress hormones affect eating behavior, and why that varies from person to person, we have all witnessed or experienced stressful situations that lead to loss of appetite or binge eating. The grieving widow who refuses to eat is a common example. So too the jilted lover who soothes their sorrow by binge eating ice cream and pastries.
Nothing I’ve written here is controversial. The effect of stress on the hypothalamus, pituitary, thyroid, adrenals and liver have been known for decades. The ability of psychological stress to contribute to poor health outcomes and shortened life span has been the subject of much research through the years. Anyone who has read Michael Marmot’s book The Status Syndrome: How Social Standing Affects Our Health and Longevity knows what I’m talking about.
Why stress escapes the notice of so many who write on weight issues fascinates me. I suspect part of the reason is that it takes the focus away from the simplistic recommendation to eat less and move more. Since most of the stress people are under emanates from factors over which they have no control, or as in the case of gut dysbiosis, are totally oblivious to, anyone peddling a system of weight loss that they expect to earn money from is apt to keep these truths hidden from their
Another possible explanation is revealed by Abigail Saguy in her book What’s Wrong with Fat?:
Supporters of a personal responsibility frame liken obesity to smoking, a behavior that is a recognized risk factor for lung cancer. This is an extremely common rhetorical strategy among the leading obesity researchers I interviewed. For instance, Theodore VanItallie drew on this analogy when asked if it was discriminatory to charge people who would be categorized as obese a higher health or life insurance premium: “I mean the same thing is true of smokers. Why should I have to pay a high life insurance [premium] because of all the deaths that are caused by cigarette smoking?” Comparing obesity to smoking implies that weight is a behavior rather than a trait that is largely beyond personal control….
…Given this, it is not surprising that doctors, obesity researchers, and official health reports typically evoke individual responsibility. A survey of 89 general practitioners (GPs) with medical practices throughout the United Kingdom showed that, on average, GPs considered their patients’ tendency to eat too much, to eat the wrong foods, or not to get enough exercise as greater contributors to their obesity than genetics, glandular/ hormonal factors, or metabolism. Another study of 255 British health care professionals arrived at a similar conclusion, finding that providers believed that physical inactivity, overeating, food addiction, and personality characteristics were the most important causes of overweight. A study of 600 general practitioners in France found that 30 percent considered overweight and obese patients to be lazier and more self-indulgent than normal-weight people, and 60 percent considered lack of motivation to be the most common problem in treating overweight and obesity. In another study of 620 primary care physicians in the United States, more than 50 percent reported viewing obese patients as awkward, unattractive, ugly, or noncompliant. One-third of the sample further characterized these patients as weak-willed, sloppy, and lazy. Similar patterns have been found in Australia and Israel. Studies have shown that nurses also assume that obesity is the product of their patients’ bad personal choices.
Walter Willett, a Harvard epidemiologist who is often quoted in the news media and who is coinvestigator of the Nurses’ Health Study, a longitudinal health study of more than 100,000 nurses, says in an interview with me that he’s “yet to be convinced that there are very many people that if they are really serious about controlling their weight, can’t get their weight down under a BMI of 25.” Similarly, JoAnn Manson, also a Harvard epidemiologist and coinvestigator of the Nurse’s Health Study, says in an interview with me that people “know if they were to get up off the couch and do some more walking … it would be helpful to them, but they just don’t feel like it.” Every day, she says, they make a choice to buy “the Big Mac and French fries instead of a salad or roasted chicken.” The 2000 World Health Organization report similarly describes obesity as “largely preventable through lifestyle changes.”
When asked to comment on studies showing that weight-loss diets have extremely low success rates over the long term, these and other obesity researchers emphasize that even a 5 to 25 percent success rate means that weight loss is possible, even if it is difficult. A group of obesity researchers have even established a “National Weight Control Registry” to follow “over 5000 people who have lost significant amounts of weight and kept it off for long periods of time,” in order to show that permanent weight loss is possible and to identify why some people are successful at long-term weight loss.
If many medical and obesity “experts” are oblivious to the well-documented effects stress has on weight dysregulation, what hope is there that the typical diet-book author or health blogger will tell you any different? Yes, eating less and moving more does lead to weight loss, but it’s typically a very short-lived phenomenon. (4) Weight Watchers® and Jenny Craig® would have long gone out of business were this not true. Many ride this dieting roller coaster for years or decades totally oblivious to how exogenous and endogenous stressors are sabotaging their heroic efforts.
These dismal results should not be surprising, especially if the cause of dysregulated weight management is from stress produced by translocating gut pathogens. Last time I checked, weight loss has no magical ability to cure gut dysbiosis.
Changing the constituents of your diet to decrease the chances of developing gut dysbiosis is most definitely worth pursuing as I’ve tried to make clear from earlier posts. That said, the best diet in the world can only lessen the chances of developing dysbiosis, not prevent it entirely. There are many things not related to diet that can cause disordered gut flora and endotoxemia like drugs, environmental toxins, surgery, viruses, contaminated food and water, and of course, psychological stress.
Now knowing how stress can affect the gut, metabolism and behavior, let’s engage in a thought experiment shall we? Let’s observe an obese middle-aged, single woman for a day.
We notice that first thing in the morning, she has trouble getting out of bed because she knows how cold she will be once she kicks back the covers and goes into her bathroom. Plus she had another horrible night’s sleep and isn’t very motivated to start the day. Her mind was racing all night with thoughts she just couldn’t stop no matter how hard she tried. She was more awake at 4 in the morning than she usually is at 4 in the afternoon.
Forcing herself out of bed, she quickly switches on the space heater in her small bathroom and turns on the shower. She showers in what most people would consider scalding hot water even though it’s the middle of summer and it’s warm inside. After drying herself off, dressing, and putting on makeup, she quickly eats her low-fat, whole-wheat cereal with skim milk and berries, careful not to go over her allotted calorie count for breakfast.
She leaves the house early because she wants to grab her favorite parking spot near the front door where she works to avoid walking more than she has to. With a BMI well over 35, walking any distance is enough to make her pant. She was also recently told by her doctor that she has osteoporosis so she is fearful of putting any more weight on her knees and hips than is necessary. And she’s still feeling a little under the weather from a cold she can’t seem to shake.
As she walks to her cubicle, she’s already shivering from the air conditioning and knows that she will need to turn on her under-the-desk space heater and put on a sweater if she’s going to make it through the day. She passes the bathroom on the way to her desk, but apart from urinating, she will probably not use it much as her bowel movements have been increasingly infrequent. Perhaps she needs more fiber in her diet she thinks to herself.
She arrives at her desk and immediately applies lotion thinking that she needs to find another product that is better at keeping her skin from drying out. While already hungry after eating breakfast barely an hour ago, she resists visiting the snack machine.
Lunch time arrives and she’s ravenous. Still keeping to her diet, she eats the whole-wheat turkey sandwich with lettuce, tomatoes, low-fat soy cheese, and low-fat safflower-oil mayo she brought with her. She also eats her raw vegetable sticks, dipping them in store-bought, ranch dressing made with soybean oil.
By early afternoon, not only is she freezing, she’s finding it harder and harder to stay focused and awake. Her “brain fog” is back. She wonders if that white coating on her tongue has any connection. Her stomach rumbles, but after visiting the bathroom, all she passes is gas. She takes an antacid hoping that will help with her bloating.
Rumors are once again swirling around the office about another staff reduction due to tough economic times. She’s already underwater on her condo and can’t imagine being without a job in this economy. Her job was spared the last time, but the rumor is that the next layoff will be even more savage than the last. She feels a headache coming on and is afraid she’ll have another panic attack if she continues discussing these rumors with her coworkers. She decides she needs a little pick-me-up and makes her way to the vending machine for some reduced-fat cookies, chips and a diet soda.
Time to go home, but first she must stop by the mall to pick up a birthday gift for a friend. Rather than park her car 20 spaces away from the front door, she waits 10 minutes until someone vacates a spot nearer the entrance. Once in the mall, she realizes the store she needs to visit is on the second floor. Rather than climb one flight of stairs, she’d rather wait for the elevator even if accompanied by a screaming baby in a stroller.
Once she arrives home, she’s exhausted. Even though it’s 80 degrees in the condo, she finally feels warm and leaves the air conditioner off. She looks at the treadmill collecting dust in the corner and tells herself she really needs to start using it again. She lost so much weight the last time she did. If only she weren’t so damn tired. Sigh…
Feeling constipated, bloated, exhausted, slightly depressed and stressed, she forgoes her reduced-calorie frozen dinner and instead picks up her cell phone and orders a pizza. Still hungry after finishing, she treats herself to a piece of store-bought, low-fat pound cake and settles down in front of the TV to watch the latest installment of The Biggest Loser, but falls asleep halfway through the show for about half an hour.
At 10 she heads to her bedroom dreading the sleepless night that probably lays ahead. She visits the toilet first and experiences her first bowel movement in two days. Turning on the exhaust fan to prevent herself suffocating from the smell, she grabs the toilet brush to scrub the sides of her bowl after flushing the first time. Why does it always stick she asks herself.
Climbing into bed, she falls off to sleep after reading for an hour only to awaken at 12:15 with partially digested pizza, cake and the acrid taste of stomach acid in her mouth. Getting out of bed, she takes a proton-pump inhibitor her doctor recommended. She falls off to sleep around 1 only to awaken at 4, tossing and turning until the alarm goes off at 7. She has trouble getting out of bed because she knows how cold she will be once she kicks back the covers…….
Knowing what you know about how stress, gut dysbiosis and endotoxemia affect so many systems of the body, does this scenario seem in the least bit far fetched? Substituting an anorexic in the preceding scenario would change nothing other than emphasize that focusing solely on weight is not likely to get you very far.
I hope this series has shed some light on how weight dysregulation can be an outward manifestation of deeper processes both in the brain and gut. Any theory of obesity that fails to take that into account is inherently incomplete and liable to lead to solutions that are at best, ineffective, or at worst, downright harmful to health and longevity.
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