What Causes Leptin Resistance?

If you have read my last blog, you'll know that leptin is extremely important in energy metabolism, managing healthy weight and keeping the thyroid in check. We are now going to explore some causative factors that can trigger leptin resistance.

The Role of Inflammation in Leptin Resistance

Firstly, fat cells are highly inflammatory. In a perfect world, fat cells should tell the body to increase sensitivity to leptin because the body has ample storage energy to burn through. This may be true up until a point. However, a nasty, negative feedback loop begins when the inflammation from those fat cells (AND OTHER FACTORS DRIVING INFLAMMATION), disrupt your leptin signalling.

Inflammation plays a crucial role in the development of leptin resistance, with fat cells (adipocytes) being a central player. Adipocytes produce molecules known as adipokines, which bridge the gap between metabolism and immune responses. Among these adipokines, leptin stands out due to its dual function as both a metabolism regulator and an inflammatory agent. When fat cells expand, they release higher amounts of leptin and other proinflammatory cytokines like adiponectin.

However, here's the twist: while leptin's primary role is to signal the brain to stop eating, chronic inflammation caused by excessive fat storage can disrupt this signaling. As inflammation increases, the body's sensitivity to leptin decreases, creating a vicious cycle: the brain no longer "hears" the leptin's stop-eating signal, leading to overeating, more fat storage, and more inflammation. This negative feedback loop further exacerbates leptin resistance and promotes continued weight gain.

In essence, the relationship between inflammation and leptin resistance is symbiotic. As adipocytes release more inflammatory molecules, the body's natural mechanisms to regulate appetite and weight are compromised, paving the way for obesity and its associated health challenges.

Circadian Dysfunction & Leptin Resistance

Next, we have the role of circadian biology in leptin regulation or resistance.

The natural rotation of the Earth around the Sun has instilled in most living organisms a rhythmic behaviour with a period of approximately 24 hours. This rhythm is governed by a system known as the circadian clock. At the core of this system is the master clock located in the hypothalamus' suprachiasmatic nuclei (SCN), which receives light signals from the retina and coordinates other peripheral clocks in the body. Any disruption to these rhythms, like those experienced during shift work, can lead to health issues such as obesity and type 2 diabetes. Recent research by Kettner et al. investigated the relationship between the circadian clock, obesity, and Leptin resistance. They used various mice models, each with distinct circadian clock deficiencies, and exposed them to normal day-night rhythms or simulated jet lag. Findings revealed that genetic and environmental disruptions to the circadian clock affected body weight and energy balance in diverse ways. Of note, Leptin, a hormone produced by fat cells that plays a critical role in appetite regulation, was directly influenced by the circadian clock. This influence was found to be via the BMAL1/CLOCK pathway, leading to rhythmic Leptin synthesis. Furthermore, Leptin levels in the blood also showed oscillatory patterns. Interestingly, people with obesity often have high Leptin levels due to increased fat cells but suffer from reduced effectiveness of Leptin, a condition known as Leptin resistance. Kettner et al. demonstrated that Leptin signaling in certain neurons is under circadian control and that disruptions to this rhythm, like chronic jet lag, could lead to Leptin resistance. This finding aligns with previous research showing that shift work affects Leptin secretion and that weight management in mice depends on synchronization between feeding and Leptin rhythms. However, the specific cause of circadian misalignment leading to Leptin resistance remains an area of active research. While several factors may induce Leptin resistance, two hypotheses seem especially relevant: alteration of Leptin signaling interconnected with the circadian clock, and endoplasmic reticulum (ER) stress, which has been associated with obesity and energy imbalance. Moreover, a disturbed lipid metabolism due to circadian clock dysfunction has been linked to ER stress. Recent findings hint that lipid metabolism in the hypothalamus shows a rhythmic pattern. Hence, a disrupted circadian clock might lead to imbalances in lipid metabolism, causing ER stress and, consequently, Leptin resistance in the hypothalamus.