Understanding the Multifactorial Etiology of Obesity and the Metabolic Adaptations to Weight Loss

Understanding the Multifactorial Etiology of Obesity and the Metabolic Adaptations to Weight Loss Posted By:
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Obesity Causes Overeating, Not the Other Way Around
One of my favorite quotes from Dr Lee Kaplan is, "Overeating does not cause obesity, obesity causes overeating." Most healthcare professionals (HCPs) were taught to instruct people to eat less and move more, when in reality, obesity is a neuroendocrine disorder that, for the majority of people, starts from an underlying propensity or susceptibility for obesity that becomes activated. When that happens, the normally tightly regulated weight regulation system no longer functions correctly. The neuroendocrine connection and endocrine system that tell us when to eat or when we have eaten enough do not work anymore, and when the brain does not receive those signals correctly, overeating slowly begins to occur.

The trigger for this dysregulation could be endocrine‑disrupting chemicals, or it could be obesogenic medications that were prescribed. That was the case in my situation. I have a family history of obesity, and when I began taking 3 obesogenic medications for a very serious cardiac problem, I also started to gain significant amounts of weight. I can pinpoint the start of my obesity to this event, which underscores that after dysregulation occurs is when people begin overeating and reinforces Dr Kaplan’s quote that obesity causes overeating. When dysfunction occurs, the body no longer regulates overeating and instead continues storing excess energy leading to the main sign of obesity, increased adiposity.

Effects of Obesity
As adiposity increases, the effects of obesity become apparent. People can develop sick fat or adiposopathy, leading to chronic inflammation from fat production of cytokines, and subsequently develop obesity‑related complications like diabetes, hypertension, and hyperlipidemia. Once visceral fat becomes saturated, it can emerge in other areas, like the liver, kidneys, and heart. Excess adiposity can cause glomerulopathy, dysrhythmias, and dysregulation of the sympathetic nervous system leading to hypertension. Therefore, it is adipose tissue, the main sign of the disease of obesity, that primarily causes obesity‑related complications. 

Symptoms of Obesity
The symptoms of obesity—excess hunger and not feeling satiety—occur because of neuroendocrine dysfunction in the tightly regulated system that no longer functions correctly. Research has demonstrated that if a person without obesity overeats, they do not eat as much the next day, and their metabolic activity is elevated. They actually have a higher basal metabolism until the excess energy they took in is burned off. 

If someone undereats, the normal response by the endocrine system is to increase ghrelin (the hunger hormone) until the person eats to raise their energy level intake back to where their body weight is within that normal tightly regulated range.

In obesity, once weight increases following neuroendocrine dysregulation, the brain considers the increased weight level as the body’s normal weight. When someone with obesity loses weight, the brain sees that as an abnormal weight loss and tells the endocrine system to increase ghrelin. Since people with obesity no longer hear satiety hormones, or the satiety hormones are decreased in level, they do not have the same response of feeling full as those who do not have obesity. As a result, people with obesity have stronger feelings of hunger and do not feel as full. In addition, their bodies initiate metabolic adaptation which decreases their total energy expenditure.

This can be thought of as a second impact of obesity, a compounding effect on the first impact of obesity, the increase in adiposity and resulting adiposopathy. The consequence of this second impact is that even if a person with obesity is successful in managing their condition, metabolic adaptation can cause them to feel excess hunger, lose or have reduced response to satiety signals, and experience lower energy expenditure. These effects can cause them to gain weight again. It is important to understand that this weight gain is not a lack of willpower, it is the result of systemic neuroendocrine dysfunction. 

Anti‑obesity Medications
Anti‑obesity medications can be effective at mitigating the impacts of obesity. They target neuroendocrine dysfunction and the effects of metabolic adaptation to not only help with weight loss but also with maintenance.

When evaluating the effects of anti‑obesity medications, the instinct is to ask how much weight the patient is losing. But very early in treatment, HCPs can better evaluate efficacy by asking the patient whether the symptoms of the disease have improved. Are they less hungry? Do they consistently feel full sooner? If they do, then the medication may be starting to work. 

HCPs should certainly ensure that patients meet the criterion of at least 5% weight loss in 12 to 14 weeks, but at least HCPs can know early on if the medications are working. I think this can help us understand the pathophysiology of the disease and how the medications impact that pathophysiology.


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Filed under: Cardiometabolic , NPs & PAs

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