Metabolic Syndrome

The diagram below details how overfeeding will lead to the so-called metabolic syndrome, a cluster of conditions that are linked and can lead to vascular disease, stroke and heart attacks.  The components of  metabolic syndrome are hypertriglyceridemia, truncal obesity, hypertension, diabetes and low HDL.  This diagram elaborates an insulin-centric model, and it’s important to recognize that there are other models.

The overfed state means the cells of the body–primarily muscle, which accounts for 80% of the body’s glucose disposal, and adipose tissue–have been overwhelmed with fuel and become overstuffed.  Insulin is an important player in this schema because glucose transport into muscles requires insulin to get nutrition into the cell.  When the cells are full, they reduce their expression of insulin-dependent glut4 transporters, making it harder to push glucose into the cell.  This resistance can be overcome by manufacturing more insulin, which is how to body initially responds to the problem of rising glucose concentrations in the extra-cellular space.  Imagine insulin to be the hose pressure pushing gas into the tank.  The more stuffed the cells are, the more insulin you need to drive nutrition intracellularly, and this is precisely the phenotype of insulin resistance.  The pancreas is the hose pump in this analogy, and with prolonged pressure, it can fail leading to diabetes.  

Meanwhile glucose that should be going into the muscles and fat cells overflows from that compartment and is instead taken up by the liver in an insulin-independent process.  In the liver, glucose is converted to saturated fat through de novo lipogenesis, ultimately leading to non-alcoholic fatty liver disease (NAFLD), which can progress to cirrhosis and ultimately liver failure.  NAFLD has become the leading reason for referral to liver transplant centers.  

Meanwhile, the very high circulating levels of insulin cause sodium retention in the kidney, creating salt-sensitive hypertension.  At the same time, insulin acts more broadly as a growth factor in the body, and high levels of circulating insulin are associated with accelerated cell division and carcinogenesis.  

This schema is the backstory of the American healthcare system.  An ever rising percentage of patients in any emergency department have hypertension, hyperlipidemia, truncal obesity and diabetes.

Metabolic Flexibility

Humans evolved in the setting of periodic food scarcity during which we developed the ability to rapidly switch between different fuel sources.  We are designed by evolution to burn fat in our fasting state and to burn primarily carbohydrates in our fed state in order to generate energy in the form of ATP.  All of this occurs in our mitochondria.  But with the development of the modern industrial food environment and ready access to overnutrition combined with less energy expenditure compared to the conditions under which we evolved, we find ourselves overnourished and at odds with our evolutionary design.  One consequence of this mismatch is impaired fuel switching in the mitochondria—we lose the ability to easily switch between lipids and glucose that marks a healthy metabolism.  As a result, our engines are inefficient, we have trouble burning fat while fasting, we are hungrier sooner after a meal, we eat more and find ourselves in a feed forward loop.  Eventually we develop obesity and the diseases related to insulin resistance such as diabetes, metabolic syndrome, NAFLD and ultimately cancer.   At least these are the claims.  What follows is an abstract of a good review paper published earlier this week that examines the concept of metabolic flexibility.

How and why does metabolic inflexibility occur?  

With chronic overnutrition (aka the Standard American Diet), cells become overstuffed and congested with macronutrients, overwhelming the enzymatic mechanisms of metabolism and leading to accumulation of incompletely oxidized substrates–the details of this process are probably not as interesting for our purposes as are the consequences.  These substrates harm mitochondria through oxidative stress from free radical damage and acetylation / protein modification due to acetyl coA accumulation.  The damage actually reduces the number of mitochondria as well as changing their functional morphology–the mitochondria look different and their performance is degraded.   The plasticity of the fuel switch deteriorates, leading to a sluggish metabolic response to nutritional cues.  Imagine a hybrid vehicle whose gas motor is flooded and so it can only use electricity.  And maybe the gas tank is expansile and is ever filling.  (I wish I could think of a better metaphor but I’m a poor mechanic).

At the same time, the overfed state also requires increasing amounts of insulin to push glucose into cells via insulin dependent glut4 transporters.  Imagine insulin to be the hose pressure pushing gas into the tank.  The more stuffed the cells are, the more insulin you need to drive nutrition intracellularly, and this is precisely the phenotype of insulin resistance.  The pancreas is the hose pump in this analogy, and with prolonged pressure, it can fail leading to diabetes.  Meanwhile glucose that should be going into the muscles and fat cells is instead taken up by the liver in an insulin independent process and converted to fat through de novo lipogenesis, ultimately leading to NAFLD–now the leading cause of liver failure.  The very high circulating levels of insulin cause sodium retention in the kidney, creating the phenotype of salt-sensitive hypertension.  Insulin is also a growth factor, and high levels are associated with carcinogenesis.  This is the backstory of the American healthcare system.

Insulin resistance and metabolic inflexibility are intertwined and it’s not clear which comes first, but they relate to each other and are both a consequence of overfeeding.  One reason this topic is of clinical interest is that people with metabolic inflexibility have problems burning fat in the fasting state.  They get hungry sooner and have trouble with fasting.   The intracellular availability of glucose determines the nature of substrate oxidation in human subjects (1).  If there is an excess of glucose, the cell will preferentially oxidize the glucose.  Otherwise it will turn to fat.

How do we treat this metabolic rigidity?

  1. Diminish the nutrition going into the cell
    1. Caloric restriction: since the problem begins with too much energy, an energy deficit, regardless of macronutrient balance, is a reasonable first step toward relieving substrate competition.  I don’t think you need to go low carb or keto, though some people may find it easier to do so in order to manage their hunger.  Calorie restriction permits cells to decongest themselves of unused substrate and restore normal membrane potential across mitochondria.  Losing weight is the best and perhaps only valid treatment for fatty liver and can reverse insulin resistance and DM2 in its early stages.  So eating less is how to repair the metabolic inflexibility which derives from eating too much–it feels like an astute observation of the obvious, but there may be a special way of eating less that is especially effective.  Fasting.
    2. Fasting: starvation has benefits beyond calorie restriction alone.  We evolved to cope with periods of starvation and the metabolic program triggered by fasting has diverse benefits beginning with exhaustion of liver glycogen stores and initiation of ketosis. Burning ketones is metabolically healthy for a number of reasons, particularly as we age.  At the cellular level, fasting induces autophagy to remove damaged proteins, mitochondrial biogenesis and mitophagy.  The issue of fasting is, of course, a larger one and care must be taken to preserve lean muscle mass, but the rationale to starting a diet with a fast is that lipid oxidation is kickstarted by more rapidly inducing metabolic flexibility.
    3. SGLT2 inhibitors:  SGLT2 (sodium glucose cotransporter-2) inhibitors force the kidneys to spill glucose in the urine leading to a condition that mimics caloric restriction.  These drugs have been shown to be kidney protective, to reduce weight, to reduce blood pressure and to improve outcomes in congestive heart failure.  It turns out that they also promote beiging of adipocytes (in mice)—the brown fat that generates heat and burns calories in the process.  Unclear if this is relevant in humans.  At the mitochondrial level, SGLT2i’s permit the cell to decongest itself of the metabolic substrates that have caused all the damage.  Taking SGLT2i at night, according to the authors, amplifies the effects of an overnight fast.
  1. Improve factors that mitigate mitochondrial stress
    1. Restoration of glutathione with glyNAC to counter oxidant stress
    2. Carnitine based acetyl-group buffering: theoretical. I don’t see any evidence that carnitine supplementation is of value at this point.
  1. Increase energy expenditure
    1. Aerobic exercise, particularly zone 2 exercise is the best way to improve the number of mitochondria and their function. There is a strong association described between exercise and metabolic flexibility.  Even after one episode of exercise, insulin resistance and mitochondrial function improve.
    2. Resistance training: bigger muscles means a bigger glucose sink, a greater buffer to accommodate nutrient load in the fed state.

 

 

Footnote

(1) https://journals.physiology.org/doi/abs/10.1152/ajpendo.1996.270.4.e733

Weight Set Point Theory

The real challenge with weight loss is keeping the weight off. 

When you lose a significant amount of weight (greater than 10% is the number that’s typically used, though certainly there is individual variability), the body does what it can to return to its original weight.  The body seems to have a functional weight set point that it defends irrespective of the extent of its internal stores of energy (in the form of fat).   The set point can increase over time because of environmental and physiological reasons.  For example, the hormonal changes of pregnancy or significant prolonged cortisol release from stress can increase the set point.  Also being placed in a new food environment such as going to college or working from home during a pandemic.  Interestingly, the set point can be raised but it does not seem to be amenable to lowering.

When we lose weight below the set point, the body counters with metabolic adaptive physiological processes that evolved to defend itself from starvation. These include the following mechanisms.

  1. Thyroid function changes.  Reverse T3 increases, T3 and T4 decrease, effectively rendering you hypothyroid
  2. Muscle efficiency increases (improved muscle function per calorie, less wasted calories)
  3. Neuro-humoral changes:  leptin, CCK, peptide YY all DECREASE, thus removing inhibitory actions on ghrelin, increasing appetite
  4. Decrease in resting energy expenditure due to weight loss and less available metabolically active tissue
  5. Adaptive thermogenesis decreases resulting in reduced resting metabolic rate
  6. Decreased sympathetic tone, increased parasympathetic tone
  7. Commitment amnesia:  relapse of maintenance behavior that were required to lose the initial weight

As a result, fewer than one out of six people who have lost a significant amount of weight can keep it off after a year. Even more alarmingly, there is a concern that by weight cycling, you end up resetting your basal metabolic rate lower across all weights.  So even after you regain the weight, you are still burning less calories, even at rest.  Why might this happen?

With weight regain, the body’s imperative can be understood as follows:  it wants to reconstitute fat free mass (FFM).  This includes lean muscle but also the weight of organs, bones and other non-fatty tissues in the body.   In Keys’ famous Minnesota weight loss experiment with conscientious objectors to WW2, over-eating and weight gain did not abate until FFM was reconstituted.  During weight regain, there was a desynchronization in the reconstitution of fat mass and fat free mass, so subjects ended up with an overshoot of fat return.  Meaning when you regain the weight, you end up with an increased percentage of fat as compared to muscle.  Fat is a less metabolically active tissue and so you should theoretically have a lower BMR at the new weight, and this is what is observed.

Is there a solution?  Possibly, and we’ll get to that.

Where does the set point reside?

How is this set point encoded and where does it reside in the body? Let’s consider two theories.

  1. Maybe there is a ponderstat–an actual sensor in the hypothalamus.  Possibly more specifically, in the arcuate nucleus of the hypothalamus, where the major nuclei relevant to maintenance of weight reside.  One theory is that specific astrocytes in the arcuate nucleus either sense changes in nutrition or somehow are attuned to loss of weight, possibly in relation to leptin levels.  As a result, they are activated in a process known as reactive gliosis.[i]  Other epigenetic changes are encoded in various parts of the brain and body as a consequence of weight loss leading to the defended phenotype.  The symptoms of this condition are excess hunger and reduced satiety as compared to normal people.  Nobody knows exactly what the thermostat is measuring.  It could be circulating fat or leptin, it could be some factor related to fat free mass.
  2. Mitochondrial theory: our energy factories are irrevocably degraded by obesity, the oxidative stress of overnutrition damages them, reducing their effectiveness and their numbers.  As a consequence, metabolism slows.  Metabolism has been functionally reset because we are not using as much fuel.  We cannot use it.

Bariatric surgery seems to evade some of the post-weight loss changes related to a set point, but only for a time and then not completely.  The commonly performed surgeries change the composition and concentration of bile-acids, which are important signals of satiety.  Also, because of structural changes in the gut, more nutrition passes to the distal part of the intestine causing increases in anorexigenic hormones such as GLP1 and PYY (hindgut hypothesis).  There may also be changes in direct signaling to the CNS.  Then the mechanical issues: the stomach is smaller, there is a fear of dumping syndrome if you eat too fast, etc.  All of these factors contribute to a functional reduction in the set point, at least temporarily.  Many people who achieve weight loss after bariatric surgery subsequently regain much of the weight.

But then how do we keep the weight off?

  1. Pacing. One basic principle is that if you must lose large amounts of weight, then do it slowly so that the body gradually adjusts to a lower set point.    Losing weight more deliberately and pausing between plateaus seems to help people evade the set point phenomenon and thus maintain reduced body weight,[ii] though to be clear, this finding is anecdotal, controversial and lacks experimental proof.
  2. Muscle.  When you lose weight, you lose both fat and fat free mass.  Fat free mass includes the weight of organs and other tissues, but also muscle.  When you regain the weight in the context of increased muscle mass, you will regain fewer pounds of fat.  In other words, muscle mass will protect against fat regain.  There are medications that should be used to mitigate the set point or even reset it. Ultimately, weight loss needs to be done in a controlled fashion with a plan, with frequent pauses to permit the body to catch up.  Muscle mass facilitates this process.
  3. Dietary characteristics. I suggest a weight diet that is somewhat less palatable, with less sugar, salt, fat and calorie density, more fiber.  The diet will be satiating but less rewarding.  If you can stick to a diet like this for a few weeks, it will change the brain reward centers and alter how you defend adiposity.
  4. Mitochondria: theoretically increasing the health and number of mitochondria will increase resting energy expenditure and may reset an elevated set point for the rationale suggested above. This would be done by zone 2 exercise and a variety of supplements that support mitochondrial biogenesis.  Also mitophagy inducers such as fasting and rapamycin.  In the future, maybe mitochondrial transplantation will be possible.
  5. Rapamycin: speaking of the namesake mtor inhibitor, it has been shown in rats to durably reset the ponderstat by unknown mechanism.
  6. Finally, no discussion of weight is complete without a mention of exercise, sleep and stress management, the famous lifestyle triumvirate.  Changing these often seems so inaccessible to people who are locked in patterns of work, parenting and life-responsibilities.

[i] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977167/pdf/main.pdf

[ii] https://www.nature.com/articles/ijo2017224

Also https://www.sciencedirect.com/science/article/abs/pii/S001650851730152X

Drugs For Obesity

Sometimes no matter how hard we exercise or how conscientiously we diet, the weight does not come off.   A short fast can jump start the process of fat oxidation, but we are also fortunate to have FDA-approved drugs to help us along if we cannot get started. Or if we plateau.   We offer medications when BMI reaches 30 (or over 27 with complications related to obesity).  Even before drugs, though, the first step is to make sure you’re not taking other prescription medications that cause weight gain.  Some of the bad actors in this realm include sulfonylureas for diabetes, certain antidepressants and antipsychotics, carbamazepine and valproate, beta-blockers and some other medications.

And before we launch on a discussion of medications, let me suggest that obesity should never be treated with just medications.  You need to establish healthy and enduring habits of nutrition and activity, otherwise the weight will just reaccumulate when you stop taking the pill.  I don’t consider a lifetime of drug therapy to be a success.

What follows is a list of the FDA-approved therapies along with my thoughts about each.  Ultimately, the decision to start medication and which one to choose is one you should make with your doctor, and it depends on each drug’s advantages and disadvantages as well as your own medical history and physiology.

    1. PHENTERAMINE:  is a stimulant, a schedule IV controlled substance, and so I’m naturally biased against it, and though there’s evidence that it is not habit-forming1, it can raise blood pressure.  It works because it reduces appetite but may be associated with anxiety, insomnia, and palpitations.  One plus is that phentermine is relatively inexpensive.  Nevertheless, there are better drugs available and I prefer not to prescribe it.  In some health systems, insurance companies require patients to fail a trial of phentermine before they will cover other more expensive drugs.
    2. PHENTERMINE / TOPIIMATE ER (QSYMIA): here we add topiramate, an anti-seizure drug with appetite suppressive properties to phentermine.  The combination is more effective than either alone and you can expect to lose about 10% of body weight after a year.   Maybe I’m less set against this one because the phentermine dose does not get as high, nevertheless, I’ve never prescribed it.
    3. ORLISTAT: here’s one that’s fairly safe, it inhibits the absorption of dietary fat, so this is a good adjunct to a low carb diet.  You can buy it in a lower dose without a prescription on Amazon, so what’s not to love?  Well, urgent, explosive, greasy stools, for one.  When you inhibit the metabolism of lipids, the fat passes through your system and changes your bathroom experience.  But if you have chronic constipation, then this might be a serendipitous plus. A second consideration is that it takes your fat-soluble vitamins with it (A,D,E,K), so you really need to supplement with a multivitamin if you’re going to take this medicine.  Most patients do not like this drug.
    4. NALTREXONE / BUPROPION (CONTRAVE): this is a fascinating drug that works by reducing hunger cravings in the brain.  Let us nerd out on the mechanism for a moment.  Bupropion is an anti-depressant that has the unexpected effect of stimulating the cleavage of a large molecule called POMC.  One of the cleavage products is a-MSH, which activates the melanocortin-4-receptor (MC4R), which reduces appetite and increases energy expenditure.  Another cleavage product of POMC, beta-endorphin, feeds-back to inhibit cleavage of POMC.  But that’s where naltrexone comes in, it blocks the inhibition of POMC cleavage, resulting in unopposed stimulation of MC4R.  Beware though that naltrexone blocks the action of opiates more broadly, so if you take opiate pain medication, this drug is definitely not for you. However, Contrave does seem to have a role in attenuating addictive pathways in the brain, so it might be an appropriate choice for someone who wants to cut down on smoking and/or drinking.
    5. GLP1 RECEPTOR AGONISTS (LIRAGUTIDE, SEMAGLUTIDE): these drugs are now both FDA approved for weight loss and they work very well.  Semaglutide has gotten a lot of press as a “game-changer” and it may actually be one—it’s a once-a-week drug that has been associated with loss of up to 20% of body weight.  The drugs imitate the effect of a molecule called GLP-1, which has a range of effects including delaying emptying of the stomach, reducing appetite, and increasing the secretion of insulin.  One would think that increased insulin is bad, but in one meta-analysis, GLP-1RA’s were associated with fewer strokes, fewer cardiovascular events, and lower all-cause mortality in a diabetic population.2  Not clear yet if this holds for non-diabetics as well, but needless to say, it makes this a very appealing medicine.  In mice, a recent article suggests GLP1RA’s reduce brain aging.3  What are the negatives?  First, the cost.  They’re expensive, but if your insurance covers them, you’re lucky.  If not, there are some other tricks to getting it at lower cost.  Second, semaglutide, while once a week, is delivered as an injection–which is a bridge too far for some.  Finally, even though the official account is that these drugs are not associated with pancreatitis, I’ve had one patient on semaglutide develop a severe case, so that experience sits in the back of my mind.  Nevertheless, these seem to be a class of agents that represent a great leap forward and a great option for people who can afford them. In all likelihood, liraglutide will go the way of the Betamax because you have to take it every day and semaglutide will be a widely prescribed drug.

Beyond these drugs that are FDA approved to treat obesity, there are metformin, SGLT2 inhibitors, and others that will afford you some weight loss and metabolic benefit and may occasionally be appropriate.  Canagliflozin, an SGLT2 inhibitor, has shown promise in the interventions testing protocol conducted by Richard Miller at the National Institute of Health as a longevity drug.  Metformin is also a promising drug for non-diabetics and is being investigated for its purported life-extension properties by Dr. Nir Barzelai.

1 (Hendricks, E. J., et al. “Addiction potential of phentermine prescribed during long-term treatment of obesity.” International journal of obesity 38.2 (2014): 292-298.)
2 Malhotra, Konark, et al. “GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis.” Journal of neurology 267.7 (2020): 2117-2122.
3Li, Zhongqi, et al. “Systemic GLP-1R agonist treatment reverses mouse glial and neurovascular cell transcriptomic aging signatures in a genome-wide manner.” Communications biology 4.1 (2021): 1-6.