The potential of GLP-1R agonists to enhance leptin sensitivity in metabolic health suggests that reducing leptin levels could improve sensitivity via hypothalamic neurons, offering a promising avenue to address obesity & diabetes.

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This story does not include health advice. It is for information, inspiration, and awareness purposes.

Hormones are crucial messengers in cells, tissues, organs, and systems in metabolic, immune, and neurological health. I extensively researched major metabolic hormones and wrote multiple stories about their functions, mechanisms, and effects. I also studied how hypothalamic neurons regulate hunger and appetite to promote healthy weight management.

Like insulin, glucagon, adiponectin, cholecystokinin, and FGF21, Leptin is another critical yet complex hormone that significantly impacts metabolic health and disease progress, especially for diabetes, fatty liver disease, and obesity. Although it might not be as potent as insulin resistance, leptin resistance is also a critical metabolic health risk based on growing literature.

Recently, when I presented my research into GLP1-RAs at a local conference, a participant said there is something magical about these molecules that gives hope to managing prediabetes, type II diabetes, fatty liver disease, and obesity, which have become epidemic globally. The informed audience unanimously agreed.

Interestingly, the word “magic,” which we rarely use in science and medicine, suddenly reminded me of a short lecture by Dr. Louis Kuritzky uploaded to YouTube three years ago.

When I asked the audience whether they had five minutes to run this educational presentation from my PC before ending it, they all said yes. After watching it, they told me my presentation became crystal clear.

Why did I write this vital piece today?

Having a leptin-resistant body when experiencing abdominal obesity and prediabetes in younger years, my journey through understanding leptin, its complexities, and its implications for health and disease has been enlightening and promising.

I decided to write this critical story because new and growing evidence indicates that GLP-1R agonism might be the answer to address leptin resistance. I explained the critical role of GLP1-RAs before.

For example, A 2023 study published in the Journal of Diabetes in the 2024 edition provided new insights into dealing with leptin resistance in a unique way examining the role of GLP-1R agonism in mice.

Some researchers, especially those studying GLP1-RAs, now believe that reducing leptin levels can lead to weight loss, and losing weight can also cause a decrease in leptin. However, the exact relationship between lower leptin levels and weight loss needs more study.

Therefore, I want to provide new findings from this recent research to inform you and inspire aspiring scientists to investigate this development that illuminates the research path and empowers clinicians.

Before that, I want to give a brief background to the hormone leptin and explain the mechanisms and impact of leptin resistance.

What is leptin, and why does leptin resistance matter briefly?

Leptin is a hormone produced by fat cells that helps regulate appetite and energy expenditure in the body. When leptin levels are high, it signals to the brain that we are full, reducing appetite and increasing energy expenditure.

When leptin signals work correctly, we stop eating naturally, as the brain creates necessary signals that turn into feelings. A leptin-sensitive body prevents overeating by opposing the hunger hormone ghrelin. More importantly, the literature indicates that low leptin levels signal hunger and decrease energy expenditure.

For example, this paper in the Keio Journal of Medicine informed that when fat mass falls, plasma leptin levels fall, stimulating appetite and suppressing energy expenditure until fat mass is restored. However, this situation is different for overweight or obese people; therefore, I wrote this follow-up story.

Leptin resistance occurs when the brain does not respond adequately to leptin’s signals, even when leptin levels are high. This can lead to persistent feelings of hunger, overeating, and difficulty losing weight.

Leptin resistance is associated with obesity and can contribute to metabolic disorders like type 2 diabetes, fatty liver disease, cardiovascular disease, some cancers, and even neurodegenerative disorders like dementia.

Addressing leptin resistance is essential for managing weight and overall health, as restoring sensitivity to leptin’s signals can help regulate appetite, promote weight loss, and improve metabolic health.

Lifestyle changes such as healthy eating, regular exercise, and adequate sleep can improve leptin sensitivity. Certain medications and treatments may also be effective in addressing leptin resistance.

I documented my personal experience in a previous story in 2022 titled Here’s How I Made My Body Leptin Sensitive and Stopped Food Cravings in 3 Steps.

Summary of New Findings from a Unique Animal Study on Specific Treatments for Leptin Resistance for Overcoming Diabetes and Obesity

In this new study published in February 2024 in Diabetes, researchers found that specific treatments such as FGF21 and Liraglutide quickly lowered leptin levels. Here’s the link to the graphical abstract of the study.

By the way, Liraglutide (like Tirzepatide or Semaglutide) is a medication used to treat type 2 diabetes and obesity by mimicking the action of a hormone called glucagon-like peptide 1 (GLP-1) to regulate blood sugar levels and promote weight loss.

This reduction in leptin mattered because it helped improve metabolic health when using Liraglutide, but keeping leptin levels high partially reduced the benefits of these treatments.

By combining FGF21 and the GLP-1R agonist Liraglutide, which lowers leptin even more, such as a leptin-neutralizing antibody, they saw even more significant weight loss and improved glucose tolerance in obese mice.

When the treatment stopped, mice typically regained weight rapidly, along with an increase in leptin levels. Using the leptin-neutralizing antibodies slowed down weight gain and maintained better glucose tolerance.

Mechanistically, reducing leptin levels made neurons in the hypothalamus more sensitive to leptin, which might help control body weight. Their findings suggest that lowering leptin levels could be an effective strategy for treating obesity and insulin resistance.

What is FGF21, and how does it relate to leptin?

As documented in the Annual Review of Physiology in 2016, Fibroblast growth factor 21 (FGF21) is a peptide hormone synthesized by several organs and regulates energy homeostasis.

The paper informs that the excitement surrounding this relatively recently identified hormone is based on its documented metabolic beneficial effects, which include weight loss and improved glycemia. I’d like to briefly summarize my knowledge of this unique hormone and its potential relationship with leptin.

FGF21 and leptin are both hormones that regulate energy metabolism and body weight, but they function through different mechanisms.

FGF21 is a protein hormone produced mainly in the liver in response to various metabolic stresses such as fasting, high sugar intake, or cold exposure. It plays a crucial role in regulating energy metabolism, glucose and lipid metabolism, and body weight.

FGF21 helps the body adapt to changes in nutrient availability by promoting the burning of fat for energy and improving insulin sensitivity. It also benefits other organs, such as the pancreas, adipose tissue, and brain.

Recent studies, such as those published in Molecular Medicine in 2018 and Frontiers in 2021, suggest that FGF21 may have therapeutic potential for treating age-related obesity, type 2 diabetes, and other metabolic disorders. Drugs that mimic FGF21's effects are being developed as potential treatments for these conditions.

FGF21 acts on various tissues to promote the burning of fat for energy and improve insulin sensitivity, thus helping to regulate body weight and glucose metabolism. While FGF21 and leptin have distinct bodily roles, some evidence suggests they may interact in specific metabolic pathways.

For example, as documented in the Journal of Molecular Sciences in 2022, FGF21 might regulate the expression of leptin receptors in the brain, and both hormones may influence common downstream signaling pathways involved in energy balance.

Dysregulation of FGF21 and leptin signaling pathways can contribute to metabolic dysfunction in obesity and other metabolic disorders. However, more research is needed to fully understand the complex relationships between FGF21, leptin, and metabolic health.

As documented in Nature and Endocrinology and Metabolism Journals, strategies aimed at improving the sensitivity of tissues to these hormones, like FGF21 analogs or leptin sensitizers, may hold promise for treating obesity and related conditions.

Summary of Leptin’s Physiological Roles in the Control of Sympathetic Nerve Activity, Energy Balance, and the Hypothalamic–Pituitary–Thyroid Axis

As it is impossible to quote hundreds of studies, in this section, I’d like to briefly summarize a comprehensive and educational review published in the International Journal of Molecular Sciences in 2023, citing many prior studies for those interested in details.

The discovery of leptin and its receptor, LepR, was significant in understanding obesity, observed in mouse models with mutations affecting these genes. Leptin levels signal energy balance through the JAK-Stat pathway, particularly in the hypothalamus.

Leptin is known as the “starvation hormone,” as decreased levels trigger hunger. Although leptin’s effects seem limited at normal levels, long-term increases induce LepR expression, enhancing its actions.

Leptin also interacts with neurotransmitters, amplifying its effects over time, particularly in brain regions like the hypothalamus and Paraventricular Nucleus. It affects sympathetic nervous system activity and blood pressure regulation.

Leptin acts in specific brain regions like the Arcuate Nucleus to control food intake and influence the cardiovascular system. It binds to receptors in the hypothalamus, particularly in the Paraventricular Nucleus, stimulating sympathetic nerve activity in various organs.

Leptin’s effects on neurons projecting to the Paraventricular Nucleus regulate food intake and energy expenditure, impacting metabolism and body weight. Increases in leptin levels can induce receptor expression, enhancing its actions over time. Leptin also affects thermogenesis after meals, potentially influencing long-term energy balance.

The development of obesity usually involves disruptions in the body’s regulation of energy balance, leading to increased fat percentage. These disruptions can stem from various factors, including genetic mutations, dietary habits, and lifestyle choices.

One hallmark of obesity is elevated hormone leptin levels, which typically signal the brain to reduce food intake and increase energy expenditure. However, in obese people, this signaling process becomes less effective due to leptin resistance.

Despite high leptin levels, the brain fails to respond adequately, allowing excess fat percentage to persist. Several mechanisms contribute to this resistance, including reduced transport of leptin to the brain and impaired responsiveness of hypothalamic neurons to leptin signals.

Additionally, obesity can trigger inflammation in the hypothalamus, further impairing leptin’s actions. Understanding these mechanisms is crucial for developing effective strategies to address obesity and its associated health risks.

An Informed Perspective from a Clinician and Obesity Expert

Recently, Dr Jason Fung, author of the NYT best-selling book Obesity Code, wrote about the role of leptin therapy in obesity.

He mentioned that Leptin was once believed to hold the key to curing obesity. Researchers hoped that increasing leptin levels would suppress appetite and lead to weight loss. However, this approach didn’t work as expected.

Dr Fung mentioned that while some people with rare genetic mutations benefited from leptin therapy, most overweight people had high levels of leptin but were resistant to its effects. This resistance was attributed to the overpowering influence of insulin, which promotes fat storage more effectively.

Like Dr Fung, I also noticed in the literature that insulin’s impact on increasing body fat outweighs leptin’s ability to reduce it, rendering traditional leptin therapy ineffective for weight loss in most cases. As a result, the research focus has shifted away from leptin as a primary target for obesity treatment, but the new research gives hope.

Conclusions and Takeaways

My journey to understand leptin and its impact on health, especially dealing with abdominal obesity and prediabetes despite having a body resistant to leptin, has been enlightening and promising.

Leptin resistance, a phenomenon in which the brain fails to adequately respond to high leptin levels, plays a significant role in obesity and metabolic disorders. Addressing leptin resistance is essential for managing weight and improving overall health.

Research into GLP-1 receptor agonists (GLP1-RAs) offers new hope for managing chronic health conditions like type 2 diabetes, fatty liver disease, and obesity by potentially addressing leptin resistance. Leptin interacts with various hormones and pathways, like FGF21, to regulate energy metabolism and body weight.

Understanding these interactions could lead to novel therapeutic strategies. FGF21 shows promising therapeutic potential for addressing obesity and metabolic disorders by promoting fat-burning and improving insulin sensitivity.

Leptin’s effects extend beyond appetite regulation, including control of sympathetic nerve activity and the hypothalamic-pituitary-thyroid axis. Understanding these complex mechanisms is crucial for developing targeted interventions.

Collaboration between scientists, clinicians, and the public is vital for advancing research and implementing effective interventions. Educational initiatives, like informative lectures and presentations, can enhance understanding and inspire progress in the field. With collaboration, innovation, and education, we can solve leptin’s mysteries and develop effective solutions for metabolic disorders.

Further research is needed to fully elucidate the complex relationship between leptin, other hormones, and metabolic health. Continued investigation into novel therapeutic targets and treatment strategies is essential for combating global obesity, type II diabetes, and fatty liver epidemics and improving public health outcomes.

Specific medications and treatments, like GLP1-RAs, FGF21 analogs or leptin sensitizers, show promise in addressing leptin resistance and promoting weight loss.

However, more importantly, lifestyle modifications, like healthy eating, regular exercise, restorative sleep, and stress management, can improve leptin sensitivity or prevent leptin resistance.

Thank you for reading my perspectives. I wish you a healthy and happy life.

If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.