By Bonnie Nedrow, ND
Metabolic Flexibility
Metabolic flexibility (MetF) is the ability to rapidly switch between oxidation of carbohydrates and fats based on nutrient availability.1 MetF allows for the storage of fuel when food availability is high and utilization of that stored energy when food availability is poor. This metabolic elasticity is critical to human survival during periods of scarcity and allows for the enjoyment and celebration of food when in abundance.
Insulin is a key player in orchestrating metabolic substrate modulation. When a meal with carbohydrates is eaten, insulin increases, which stimulates oxidation of glucose and storage of both carbohydrates and fatty acids. In a eucaloric state, where food intake matches fuel expenditure, an individual will neither gain nor lose weight. When caloric intake exceeds fuel needs, excess calories are stored as fat to be accessed at a future date to fuel sub-caloric periods of time.
Historically, humans have repeatedly experienced periods of both feasting and famine—to some extent seasonally each year and with extended intervals of low caloric intake during lean years and excess consumption during plentiful years. This variation in caloric intake is also seen on a much smaller scale in the daily cycle of the fasted/fed states. On a daily basis, it is common for people to fast overnight for roughly 10-12 hours: a period longer than can be sustained by glucose metabolism alone. In lean healthy individuals, fatty acid oxidation increases during the overnight fasted state. Following a meal with carbohydrates, these individuals secrete insulin, thereby suppressing fatty acid oxidation and shifting metabolism to primarily glucose oxidation.2 The daily fast/fed cycle in this example demonstrates metabolic flexibility.
When healthy lean people are exposed to prolonged fasting or prolonged exercise, fatty acids and ketones increase and energy is maintained despite an imbalance of fuel intake and expenditure. These are other examples of how MetF maintains optimal function despite environmental unpredictability.
Metabolic Inflexibility
Metabolic inflexibility (MetIF) is a modern malady linked to metabolic syndrome and to many chronic diseases. While it may seem obvious that overconsumption of calorie-dense food is the root cause, it turns out to be much more complicated. Other key contributory insults include poor sleep combined with high stress, environmental toxicants (chemicals that are detrimental to health), poor exercise habits, and a mismatch of activity to circadian rhythms. To reinstate metabolic flexibility in metabolically ill people, all these factors must be addressed.
Insulin, the conductor of metabolic substrate modulation, does not have the same impact on people who are obese and insulin resistant. Contrary to metabolically well people, this metabolic type shows reduced fatty acid oxidation in general, a lack of increase in fat burning during the fasted state, and minimal suppression of fat metabolites with an increase in insulin. These people end up with excess fuel in their blood stream and in storage but lack the ability to easily burn either glucose or fat. They are overweight, fatigued, and inflamed from this excess that does not fuel their body.
Someone who has become metabolically inflexible cannot easily mobilize fat from storage. Instead, they become dependent on frequent meal spacing to stay fueled with carbohydrates. This is driven by neuropenia, a shortage of glucose in the brain, usually due to transient hypoglycemia. It becomes increasingly difficult to stay on a eucaloric diet and nearly impossible to sustain a sub-caloric diet to achieve weight loss and re-establish metabolic flexibility. What was an advantageous metabolism for a world where food security was uncertain has become a curse in a society where abundant food is driving metabolic disease.3
Metabolic Syndrome
As stated earlier, MetIF is associated with metabolic syndrome (MetS): the clinical presentation of a human system on the verge of chronic disease. Diseases associated with this condition include diabetes, obesity, cardiovascular disease, Alzheimer’s, and non-alcoholic liver disease. MetS is defined as elevated blood pressure, truncal weight gain, high fasting glucose, high fasting triglycerides, and low HDL. More recently, elevated liver enzymes, in particular alanine aminotransferase (ALT) and gamma-glutamyl transference (GGT), have been added to the list of biomarkers associated with MetS. Looking beyond the clinical definition, metabolically ill people experience the all-too-common symptoms of weight gain, fatigue, and inflammation throughout their body. According to the National Health and Nutrition Examination Survey (NHANES), the incidence of MetS increased by 35% between 1998-2012 and is a common presentation in a large percentage of patients seeking medical care today.
| Test | Optimal | Metabolic syndrome |
| HDL | >50 | <50 women/<40 men |
| Triglycerides | 50-90 | >150 |
| Fasting glucose | 60-90 | >99 |
| ALT | teens | >23 women/>25 men |
| GGT | teens | >20 |
| Hip/waist | 0.8 or less | >0.85 women/>1.0 men |
| BP | 60-75/120-125 | >80/130 (either value) |
Obesogens
In the past several years, the general knowledge and recognition of the health impacts of endocrine disrupting chemicals has grown. However, the well documented phenomenon of obesogens, a sub-class of endocrine-disruptive compounds, has been slower to be recognized. Given the world-wide epidemic of obesity and the comorbidities associated, there is a growing need for clinicians to incorporate diagnostic and therapeutic modalities aimed at a reduction of both exogenous and endogenous exposures to this class of compounds.
Obesogens are chemicals that interfere with healthy metabolic regulation through promotion of adipogenesis and induction of fat storage. One of the most studied mechanisms for these effects is the peroxisome proliferator-activated receptor PPAR-γ. PPAR-γ programs increased adipocyte number and size in the developmental years as well as promoting lipid accumulation and storage in adults. Additionally, there are many steroidal endocrine disruptive compounds that also induce obesity. Exposure to obesogens during development predisposes an individual to increased susceptibility to these same chemicals at a later date. In this fashion, long-term exposures to obesogens from conception onward drives the obesity epidemic.4
