Leptin Resistance

We have briefly discussed Leptin in our earlier blog. Today we are going to discuss Leptin in detail & the role of genetics.

Leptin is a hormone secreted by our fat cells (adipose tissues). It plays an important role in energy balance & regulation of body weight.

Leptin’s main function is to interact with Brain & signal how much chemical energy is stored as fat. Based on this signal, the brain alters how much energy we take from food & expend on processes which are not required for immediate survival such as growth & reproduction.

The more fat ( adipose) tissue we carry , the more leptin we produce. When Leptin acts on the brain, it suppresses calorie intake (reduced consumption of food/drinks) & increases energy expenditure (burning more calories by releasing heat energy). Disruption to the function of Leptin is associated with weight gain & obesity.

Besides acting as a hormone that regulates energy balance, Leptin also causes inflammation. We can describe Leptin as a pro-inflammatory cytokine (cell signalling molecule).

Despite fluctuations & variations in the food we eat & the energy we extend, our body weight remains relatively stable over time (this is partly the reason why people fail to maintain weight loss & often end up regaining lost weight). This is because body weight & energy balance is regulated by a process called Homeostasis (maintaining a constant internal environment). Leptin plays a key role in maintaining the fine balance between energy we get from our diet & energy we will expend on all the bodily processes necessary to survive. Our body has an in-built lipostat that regulates the amount of energy we store in fat cells. Leptin acts a feedback signal for Lipostat.

When our body consumes more energy that it burns (old calorie in- calorie out rule), the excess energy is stored in fat cells (adipose tissue) which leads to weight gain. If this process continues, our body weights will further move away from set point. To manage this, our fat cells (adipose tissue) secrete Leptin that signals to the brain that our body has excess energy stores. In turn, the brain acts on these signals & orchestrates reduction in energy consumption/ food intake & increases energy expenditure. This allows our body to correct our energy balance & revert bodyweight back to its original position. In order words, when our body has abundance of energy (high food intake), Leptin makes our body to use the excess energy in other processes such as growth & reproduction (rather than storing excess energy as fat tissues).

How does Leptin suppress appetite?

Leptin acts on structure within the brain & suppresses food intake by stimulating the release of appetite suppressing hormones & inhibiting the release of appetite stimulating hormones in the brain circuit that regulates feeding behaviour.

Besides, Leptin also increases our energy expenditure through various metabolic processes such as thermogenesis- rate at which chemical energy gets converted into heat energy. Leptin increases this rate. One tissue that plays an important role in thermogenesis is adipose tissue, specifically brown adipose tissue (BAT). When BAT is released, Leptin activates a special part of the nervous system- sympathetic nervous system(SNS). As a result, brown fat cells (adipocytes) increase the rate of heat production & a greater proportion of chemical energy from food is lost as heat energy.

SNS also regulates our cardiovascular system. When SNS is activated, Leptin increases our heart rate & blood pressure. When our heart pumps at a faster rate, it increases our energy expenditure.

Let us talk about Leptin Resistance in detail.

As discussed above, Leptin is released by fat cells & the more fat cells (adipose tissues) we have, the more Leptin we produce. Therefore an obese individual produces more Leptin than a lean individual. So the question arises, if Obese individuals produces more Leptin, then how come they are fat & obese. Going by the theory, with high circulatory levels of Leptin, obese people have low apetite & high energy expenditure which should lead to weight loss. How do we reconcile this discrepancy? The reason is Leptin Resistance.

Overweight & obese people are resistant to effects of Leptin. Although obese people have high level of Leptin, their brain & other tissues does not adequately suppress appetite & increase energy expenditure.

So what causes Leptin resistance?

Leptin must be transported from the bloodstream across a protective membrane known as the blood brain barrier before it acts on neurons in the brain. Two forms of Leptin receptors are responsible for transport of Leptin – LEPRa & LEPRb. Leptin resistance may also occur due to default in this Leptin transport process. The following can be reasons for Leptin resistance:

As shared earlier, Leptin impacts food intake & energy expenditure by binding to Leptin receptors on various cells including neurons in the brain. However, these cells have fewer LEPRb receptors, they will be less sensitive to effects of Leptin. Reduced number of LEPRb receptors is a potential cause of Leptin resistance.
Disruption to enzymes, receptors & various other molecules involved in Leptin resistance signalling can lead to Leptin Resistance. Such disruption may be caused by inflammatory responses that impair Leptin receptor signalling.
Leptin modifies various circuits of the brain & stimulates them to suppress appetite. These circuits rely on MSH & MC4R receptors as signalling proteins. Defects in these target circuits can make the impact of Leptin less effective.
Let us now discuss role of Genetics in Leptin resistance

Mutation of Leptin related genes can directly cause obesity however these mutations are very rare. A rare mutation of Leptin related Gene, LEPR which encodes a Leptin receptor can cause Leptin Resistance Deficiency. People with these deficiency do not produce Leptin Receptor due which they are completely insensitive to Leptin. People with such rare mutations have problems with sexual development & fertility.

One common variant of LEPR gene is associated with Leptin resistance & increased risk of obesity. This gene variant causes lower expression of LEPRb receptors. Besides, the CRP gene also impacts the Leptin signalling. This gene encodes a protein called C-reactive protein which plays a role in inflammation. Increased levels of CRP in bloodstream can disrupt pathways in Leptin receptor signalling thereby increasing risk of Leptin resistance.