Adipokine Balance: How fat coordinates metabolism

by Jessica Freed
figures by Corena Loeb

Have you ever wondered why losing weight can be so challenging? Or how obesity contributes to the development of type 2 diabetes?

Over the past three decades, groundbreaking research has completely transformed our understanding of fat, which is stored in the body as adipose tissue. Once thought of merely as a storage site for excess energy, adipose tissue has recently emerged as a powerful command center that coordinates many processes throughout our body. It does this by releasing signaling proteins, known as adipokines, into the bloodstream.

Adipokines travel through the bloodstream and reach other organs to influence their metabolism. Metabolism refers to all chemical processes in the body which sustain life. Metabolism includes processes like converting food into energy, producing cellular components, and breaking down stored energy for use.

So, why should we care about adipokines? Adipokine signaling is a delicate balance that promotes metabolic health (Figure 1). Metabolic health refers to the ability of the body to properly respond to energy changes like eating a meal. On the other hand, imbalanced adipokine signaling can disrupt this ability, leading to metabolic diseases like type 2 diabetes.

**Figure 1.** Adipokines are released from adipose tissue into the bloodstream and travel to other organs to regulate their functions.

To better understand how adipokine signaling impacts health and disease, we’ll first take a close look at two of the most important adipokines: leptin and adiponectin. From there, we’ll explore how groundbreaking medications like Ozempic and Wegovy may influence adipokine balance, and what remains to be studied in this rapidly evolving field.

Leptin

Leptin, the first adipokine discovered in 1994, signals that there are sufficient energy stores, leading to feelings of fullness. After release from adipose tissue, leptin travels through the bloodstream and binds to receptors in tissues like the brain. By binding to receptors in the brain, leptin leads to appetite reduction (Figure 2).

Leptin levels circulating in the blood are directly related to the amount of body fat an individual has: more body fat produces higher levels of circulating leptin. Therefore, during weight loss, circulating leptin levels drop significantly. This decrease in leptin triggers a “starvation response” that increases appetite and slows metabolism, contributing to weight regain. Decreased leptin during weight loss can therefore make continued weight loss more difficult.

Because leptin leads to appetite suppression and increased energy expenditure, scientists initially thought that leptin treatments could be used for weight loss. However, clinical trials have shown that leptin treatments do not cause significant weight loss in most obese individuals. This paradox is due to “leptin resistance,” a condition where the body no longer responds to leptin properly (Figure 3). Leptin resistance is associated with obesity, and it results in the brain mistakenly perceiving a lack of leptin despite high levels of leptin in the blood. This can lead to further weight gain due to chronically increased appetite and decreased energy expenditure. Thus, understanding how to prevent or reverse leptin resistance is an area of active research with major implications for the treatment of obesity.

**Figure 3.** In obesity-associated leptin resistance, high levels of circulating leptin are ineffective at signaling to the brain and other tissues. This results in increased appetite, suppression of energy expenditure, and weight gain despite sufficient energy stores. This is similar to what is seen in weight loss, where reduced circulating leptin leads to weight regain.

Adiponectin

Discovered a year after leptin, adiponectin is the most abundant adipokine in the bloodstream and has a unique role in promoting insulin sensitivity. Insulin sensitivity refers to the proper function of insulin, a hormone that signals to tissues in the body to absorb blood sugar when it is high. Adiponectin contributes to insulin sensitivity by increasing insulin production and blood sugar uptake.

Type 2 diabetes is caused by insulin resistance, the inability of insulin to properly lower blood sugar. Unlike leptin levels, adiponectin levels are typically lower in individuals with obesity. These lower adiponectin levels cause decreased insulin sensitivity, promoting insulin resistance. Therefore, decreased adiponectin is one link between obesity and type 2 diabetes. Medications that treat type 2 diabetes often increase adiponectin levels.

Adiponectin also has beneficial roles in reducing inflammation. Inflammation refers to the condition of swelling and pain in the body. Inflammation is caused by the accumulation of immune cells. These immune cells can also release proinflammatory proteins that further promote inflammation. Adiponectin reduces inflammation by decreasing the proinflammatory proteins released by immune cells.

Although inflammation is important in the healing process, obesity is associated with chronic inflammation that is independent of injury or infection. This chronic inflammation intensifies many conditions including heart disease and asthma. Decreased adiponectin levels in obesity further increase inflammation and its complications. Therefore, effectively boosting adiponectin levels in obesity is key in reducing the risk of severe health problems.

Adipokine Balance in Metabolic Health and Disease

As exemplified with leptin and adiponectin, maintaining adipokine balance is essential for metabolic health. Since leptin and adiponectin’s discoveries, over a hundred different adipokines have been identified, each of which play important roles in regulating inflammation, insulin sensitivity, body weight, and more. These adipokines can generally be grouped into two categories: proinflammatory (such as leptin) and anti-inflammatory (such as adiponectin).

In obesity, there is often a disruption of adipokine balance, with increased proinflammatory adipokines and decreased anti-inflammatory adipokines. Reflecting this, low adiponectin to leptin ratios (indicating lower adiponectin levels and higher leptin levels) are correlated with insulin resistance, type 2 diabetes, and metabolic disease risk (Figure 4).

**Figure 4.** Obesity and type 2 diabetes reflect a shift in the balance of pro-inflammatory and anti-inflammatory adipokines, leading to additional metabolic consequences.

Because dysregulated adipokine levels in obesity are tied to the progression of metabolic diseases, medicines that regulate adipokine balance are particularly promising. One exciting example of this is found in prescriptions like Ozempic and Wegovy.

GLP-1 Agonists and Adipokine Balance

Metabolic conditions such as obesity and type 2 diabetes increase the risk of serious health complications such as heart attack and stroke. Recently, Ozempic and Wegovy have become increasingly popular treatments for type 2 diabetes and obesity. Ozempic and Wegovy are both examples of GLP-1 agonists, meaning that they mimic the effects of GLP-1, a naturally occurring hormone released by the small intestine. GLP-1 agonists activate GLP-1 receptors throughout the body, reducing appetite, digestion speed, and blood sugar levels. GLP-1 agonists have also been shown to restore adipokine balance by reducing leptin levels and increasing adiponectin levels, bringing them closer to levels found in healthy individuals.

GLP-1 agonists have been shown to help patients lose a striking amount of body weight– on average 15 to 20 percent. However, one challenge is that patients often regain weight after they stop taking these medications. While the exact reasons for weight regain remain unclear, one proposed explanation is that GLP-1 agonists decrease circulating leptin levels, triggering the starvation response. This causes an increase in appetite and a decrease in energy expenditure, promoting weight gain once the medication is discontinued. Although this hypothesis remains to be tested, it highlights the complicated nature of adipokine balance. Once the body is adjusted to high leptin levels (and is likely leptin resistant), simply reducing leptin levels may not be enough to promote sustained weight loss. Further research on Ozempic and Wegovy’s long-term effects on adipokine signaling is needed to ensure that these treatments are both effective and sustainable.

By recognizing adipokines as important coordinators of our body’s metabolism, we can gain a deeper understanding of how adipokine signaling supports our health. Similarly, by understanding how adipokine balance becomes disrupted in obesity and type 2 diabetes, we can engineer new treatments that restore healthy adipokine levels. As research into adipokine signaling advances, it holds the potential to unlock more effective treatments that address the root causes of metabolic diseases. This could ultimately improve the lives of millions of people worldwide, offering hope for a healthier future.

Jessica Freed is a student in the PhD Program in Biological Sciences in Public Health at Harvard.

Corena Loeb is a Ph.D. student in the Harvard-MIT program in Speech, Hearing, Bioscience and Technology.

Cover image by viarami on PixaBay.

For More Information:

Check out this brief YouTube video that introduces adipokines and their obesity-associated dysregulation.
These articles from the Cleveland Clinic discuss the adipokines leptin and adiponectin in greater detail.
This YouTube video briefly discusses the use of GLP-1 agonists for weight loss.