Final Report Summary - SOLVING CKD (Protecting against obesity-induced chronic kidney disease using pro-resolving lipids)
‘Obesity poses one of the most serious public health challenges’, according to WHO. Indeed, obesity related co-morbidities substantially increase mortality. As the obesity epidemic continues to spread across Europe, an alarming increase in obesity-induced organ disease follow in its wake. Interestingly, inflammation appears to be a critical driver of obesity-related diseases.
Inflammation is regulated by ‘turn on’ and ‘turn off’ switches, both equally important to maintain health. Most often, inflammation is a healing response to an injury. For instance, an infection induces ‘turn on’ signals, resulting in the recruitment of white blood that kill the pathogen causing the infection. However, as the infection subsides, the inflammatory response must be turned off; otherwise the inflammation will end up injuring the host. ‘Turn off’ signals may be induced by a family of lipids, called specialized pro-resolving mediators (or “SPMs”). SPMs calm the white blood cells and switch their behavior from a pro-inflammatory to an anti-inflammatory state. This shift in phenotype enables the white blood cells to clean up the after the inflammation and return the tissue to homeostasis, a process called inflammatory resolution.
In obesity, constantly raised sugar levels and the physical expansion of the fat tissue function as ‘turn on’ mechanisms, triggering a chronic inflammatory state. Our research investigates the potential of using one specific SPM, called lipoxin, as a therapeutic to boost the body’s natural ‘switch off’ mechanism and prevent obesity-induced diseases.
We recently published a study in the journal Cell Metabolism, demonstrating the therapeutic potential of lipoxins in obesity-related disease. We used an experimental model, were mice subjected to a 3 month long high-fat diet (60% fat) develop organ dysfunction, particularly in the liver and kidneys. The lipoxins were given in an interventional manner, for the last two months of the diet regime. The lipoxin treatment significantly reduced inflammation in the fat tissues and improved kidney and liver disease (Figure 1). As characteristic of the lipoxins, they promoted an anti-inflammatory phenotype in the white blood cells, specifically promoting what we call a “M1 pro-inflammatory to M2 anti-inflammatory switch” in the macrophage phenotype. (Macrophage are a type of white blood cell that can be both ‘good guys’ and ‘bad guys’ in the resolution process, depending on their phenotype). The M1-to-M2 phenotype switch resulted in a dramatic drop in pro-inflammatory mediators (TNF-a), while anti-inflammatory mediators (Annexin-A1) were upregulated. Another very interesting and novel finding was that lipoxins restored a process called ‘autophagy’, which is downregulated by overfeeding and correlates with inflammation. As lipoxins ‘turn off’ the inflammation in fat tissue, the animals stopped developing fatty liver disease (evidence: reduced triglycerides and serum ALT levels) and kidney disease (evidence: reduced scar tissue, less protein and oxidative products in urine).
Importantly, the lipoxin-mediated organ protection occurred without any loss in body weight, highlighting that lipoxins is not a “diet drug”, but rather effects the biology of the tissues to behave in a more healthy and non-inflamed manner. Overall, the lipoxin protected against obesity-induced organ damage, without noticeable side-effects. Finally, early evidence suggest that lipoxins can reduce inflammation in human fat tissue, in a similar way as it did for mice. Our ultimate hope is that these findings can be used to create a lipoxin-based drug for obese people to help protect them against associated illnesses, such as kidney and liver disease.
If we could help obese patients avoid the dangers of obesity and inflammation-fueled disorders, thereby remaining over-weight but relatively healthy, this would have substantial social-economic impact.
Inflammation is regulated by ‘turn on’ and ‘turn off’ switches, both equally important to maintain health. Most often, inflammation is a healing response to an injury. For instance, an infection induces ‘turn on’ signals, resulting in the recruitment of white blood that kill the pathogen causing the infection. However, as the infection subsides, the inflammatory response must be turned off; otherwise the inflammation will end up injuring the host. ‘Turn off’ signals may be induced by a family of lipids, called specialized pro-resolving mediators (or “SPMs”). SPMs calm the white blood cells and switch their behavior from a pro-inflammatory to an anti-inflammatory state. This shift in phenotype enables the white blood cells to clean up the after the inflammation and return the tissue to homeostasis, a process called inflammatory resolution.
In obesity, constantly raised sugar levels and the physical expansion of the fat tissue function as ‘turn on’ mechanisms, triggering a chronic inflammatory state. Our research investigates the potential of using one specific SPM, called lipoxin, as a therapeutic to boost the body’s natural ‘switch off’ mechanism and prevent obesity-induced diseases.
We recently published a study in the journal Cell Metabolism, demonstrating the therapeutic potential of lipoxins in obesity-related disease. We used an experimental model, were mice subjected to a 3 month long high-fat diet (60% fat) develop organ dysfunction, particularly in the liver and kidneys. The lipoxins were given in an interventional manner, for the last two months of the diet regime. The lipoxin treatment significantly reduced inflammation in the fat tissues and improved kidney and liver disease (Figure 1). As characteristic of the lipoxins, they promoted an anti-inflammatory phenotype in the white blood cells, specifically promoting what we call a “M1 pro-inflammatory to M2 anti-inflammatory switch” in the macrophage phenotype. (Macrophage are a type of white blood cell that can be both ‘good guys’ and ‘bad guys’ in the resolution process, depending on their phenotype). The M1-to-M2 phenotype switch resulted in a dramatic drop in pro-inflammatory mediators (TNF-a), while anti-inflammatory mediators (Annexin-A1) were upregulated. Another very interesting and novel finding was that lipoxins restored a process called ‘autophagy’, which is downregulated by overfeeding and correlates with inflammation. As lipoxins ‘turn off’ the inflammation in fat tissue, the animals stopped developing fatty liver disease (evidence: reduced triglycerides and serum ALT levels) and kidney disease (evidence: reduced scar tissue, less protein and oxidative products in urine).
Importantly, the lipoxin-mediated organ protection occurred without any loss in body weight, highlighting that lipoxins is not a “diet drug”, but rather effects the biology of the tissues to behave in a more healthy and non-inflamed manner. Overall, the lipoxin protected against obesity-induced organ damage, without noticeable side-effects. Finally, early evidence suggest that lipoxins can reduce inflammation in human fat tissue, in a similar way as it did for mice. Our ultimate hope is that these findings can be used to create a lipoxin-based drug for obese people to help protect them against associated illnesses, such as kidney and liver disease.
If we could help obese patients avoid the dangers of obesity and inflammation-fueled disorders, thereby remaining over-weight but relatively healthy, this would have substantial social-economic impact.