New brain mechanisms regulating body weight identified: Rodent study

Summary: Interleukin-6 interacts with leptin in the lateral parabrachial nucleus to reduce food intake. Reducing IL-6 in the IPBL increases weight gain and could help explain why some are more prone to overeating and obesity.

Source: University of Gothenburg

Researchers at University of Gothenburg, Sweden, clarify the link between the molecule interleukine-6 (IL-6) in the brain and obesity. In experiments on rats and mice, they show that the molecule does affect the risk of obesity, and also where this effect occurs in the brain.

Interleukine-6 (IL-6) is a well-known pro-inflammatory molecule and an integral element of the body’s first line of defense during infection. Intriguingly, the brain may govern and utilize IL-6 differently from the rest of the body.

Researchers led by the laboratory of Karolina Skibicka at the Sahlgrenska Academy, Sweden, asked: what happens to IL-6 levels in the brain following a diet that leads to obesity?

Rats and mice were offered a high-calorie palatable food, a mix of fat and sugar, in addition to their regular low-calorie diet. Like many humans, rodents choose to overeat when presented with calorie dense foods.

“What we found was that the rats and mice that became obese, had reduced IL-6, but only in one brain region, called Lateral Parabrachial Nucleus (lPBN)”, says Devesh Mishra, postdoctoral fellow leading the study.

“To understand whether this reduction of IL-6 is a good or bad thing for the metabolic health of the rodents, we viro-genetically reduced IL-6 levels very selectively in the lPBN; this led to increased body weight and body fat, even in rodents fed a healthy diet”.

Therefore, the researchers conclude that the reduced levels of lPBN IL-6 in obesity are problematic, and likely contribute to metabolic dysfunction and weight gain.

Since body weight is a result of how much we eat i.e. energy intake and how much energy we use (energy expenditure), weight gain can follow dysfunction of either one of these branches of energy balance.

What makes local parabrachial nucleus-produced IL-6 extra important, the study found, is that it affects both branches simultaneously. It decreases food intake and increases energy expenditure, the latter by increasing brown fat activity, so the body’s energy is utilized for heat generation or fat burning. Hence reduced levels of lPBN IL-6 disrupt the entire energy balance equation.

This shows a weighing scale, a tape measure and an apple
The researchers conclude that the reduced levels of lPBN IL-6 in obesity are problematic, and likely contribute to metabolic dysfunction and weight gain. The image is in the public domain.

These findings may be relevant not only for mice but also people, since an earlier study from University of Gothenburg, revealed that blood serum IL-6 levels in obese and overweight men are increased, yet brain IL-6 levels, measured in cerebrospinal fluid, are reduced.

There is one unsolved piece of the puzzle in these new findings – researchers found that the obesity-associated reduction in IL-6 was only present in males. Female rats and mice had normal IL-6 levels. The Sahlgrenska team is now investigating why females are protected from the obesity-associated IL-6-driven dysfunction.

Given that obesity is a major global disorder, with 1.9 billion overweight individuals out of which 650 million are obese, new effective anti-obesity treatment are desperately needed.

On the scientific end, we think that IL-6 could be a satiety mediating substance with a brain region specificity. This may be an important discovery which can open new doors in the quest for more effective anti-obesity strategies.

About this neuroscience research article

Source:
University of Gothenburg
Media Contacts:
Devesh Mishra – University of Gothenburg
Image Source:
The image is in the public domain.

Original Research: Open access
“Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism”. Devesh Mishra et al. Cell Reports. doi:10.1016/j.celrep.2019.02.044

Abstract

Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism

Highlights
• Obesogenic diet robustly reduces, and 4°C cold exposure increases, rodent lPBN IL-6
• IL-6 interacts with leptin at the level of the lPBN to reduce food intake
• LPBN IL-6 leads to increased BAT thermogenesis by thyroid and sympathetic mechanisms
• Reduction in lPBN IL-6 increases weight gain and adiposity

Summary
Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6.

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