"Why Doesn't My Appetite Decrease?"... After Insulin Resistance Comes 'Leptin Resistance'? [Professor Ahn Cheol-woo's Encyclopedia of Hormones]

[Financial News]Hormones have been passed down and developed from species to species alongside the evolution of life. If there is one chemical substance that must exist as long as life exists, it is the hormone. In that sense, hormones are immortal. Through this column, Professor Ahn Cheol-woo aims to provide accurate information about hormones, the chemical substances that govern the body, and suggest ways to live a healthier and happier life.  
What effect does insulin have on the complex mechanisms of leptin and ghrelin?
Just as insulin affects dopamine circuits, ghrelin and leptin also affect these circuits. Ghrelin binds to receptors in dopamine circuits, prompting the release of more dopamine, while leptin reduces dopamine release and weakens dopamine-dependent behaviors such as food cravings and drug addiction.
According to one study, showing images of food to people with insufficient leptin secretion causes excessive activation of the ventral tegmental area. However, when leptin is injected into them, this response decreases, as does their desire for food.
Leptin, ghrelin, and insulin may be part of a reward system that prevents dopamine from being released in excessive or insufficient amounts. The ventral tegmental area of the midbrain, where dopamine circuits develop, along with the hypothalamus and brainstem, may be sites where peripheral hormones involved in signaling converge and work together. If we can fully understand this integrated mechanism, we may not only find clues to obesity but also discover ways to address tobacco and drug addiction.
That is because the system that manages appetite ultimately manages addiction. The appetite-suppressing hormone leptin is secreted by fat cells. Naturally, the more body fat there is, the more leptin is secreted. This raises a question.
People with obesity should secrete more leptin, so why can’t they control their appetite? The theory that explains this is called 'leptin resistance.' Fat cells secrete sufficient leptin, but receptors in the arcuate nucleus of the hypothalamus do not bind to leptin.
In 1995, a research team in the Department of Endocrinology at Beth Israel Deaconess Medical Center (BIDMC) in Boston, Massachusetts, first proposed this concept. The team placed mice on an extremely high-fat diet to make them obese. As the mice gained fat, they secreted more leptin. However, they showed no intention of reducing their food intake and instead became even fatter. The fact that their appetite remained unchanged despite increased leptin suggested that, for some reason, leptin was not working in the brain.
The research team named this phenomenon 'leptin resistance.' Several years later, another research team examined leptin levels in people with obesity and found that they were much higher than those in people of normal weight. In obese mice with a mutated leptin gene, administering leptin suppressed appetite. However, giving leptin to people with obesity who already had high leptin levels produced little effect on appetite reduction or weight loss.
These findings established the concept of 'leptin resistance': becoming obese and secreting excessive amounts of leptin leads to resistance. The concept of leptin resistance reminds us of 'insulin resistance.' In insulin resistance, the pancreas secretes sufficient insulin, but receptors or cells in the liver, muscles, and other tissues do not respond to it. The more a person eats, the more insulin is secreted, and when it becomes less effective, the pancreas works desperately to produce even more. The same pattern applies: the more this happens, the more severe the resistance becomes.
Recent research shows that obesity, elevated leptin levels, leptin resistance, and insulin resistance are interconnected. In 2020, a Pakistani research team tested and compared the blood of an obese group with a BMI of 25 or higher and a normal-to-overweight group with a BMI of 25 or lower. The obese group had leptin levels 5.6 times higher than those of the normal-to-overweight group. Fasting plasma insulin levels, which indicate insulin resistance, were also 1.2 times higher in the obese group.
The problem is that high leptin levels caused by obesity further worsen insulin resistance. Among the hormones secreted by fat cells is adiponectin, which promotes the use of fat as fuel during prolonged fasting. Adiponectin has anti-inflammatory effects and suppresses the expression of various inflammation-related factors. However, as abdominal obesity becomes more severe, adiponectin secretion decreases while leptin secretion increases.
Leptin, in contrast, promotes the expression of inflammatory cytokines, worsening insulin resistance. These findings show that obesity is the starting point of all these problems. Without obesity, leptin resistance would not develop; without leptin resistance, insulin resistance would not worsen and progress to diabetes. To preserve leptin’s inherent appetite-suppressing function, we should always monitor how much we eat and put down our spoon once we feel moderately full.
Diabetes is a more painful disease than many people realize. Patients must spend their lives struggling between appetite and blood sugar and face the possibility of complications. If people carefully manage their body mass from their 40s and 50s, when weight gain typically begins in earnest, and lower their risk of diabetes, their quality of life in old age will improve significantly.

/ Ahn Cheol-woo, Professor of Endocrinology, Gangnam Severance Hospital

[email protected] Medical Specialist Jung Myung-jin Reporter