Metabolic

Blood vessels could make you fats and nonetheless match

Fatty acid transporter (CD36; blue) in blood vessels (green), the overlap of which is shown in yellow-green, across fat cells (red) under the skin. Credit: IBS

Healthy obesity begins where metabolic disorders occur: the interaction between the vessels and fat enables more selective, selective fat storage in a healthier way.

Can Obesity Define Health? It’s a question for a lot of debate. Still, obesity is broadly divided into metabolically healthy obesity (MHO) and an unhealthy version of obesity. As we get older, as we age, we tend to put on more fat around the waist than around the hips and legs, becoming “apple-shaped” rather than “pear-shaped,” and also being at higher risk for metabolic syndrome. Because fat accumulates around our abdominal organs rather than under the skin where most of our body fat is normally found, this visceral fat releases fatty acids and inflammatory substances directly into the liver, leading to toxicity and insulin resistance. Meanwhile, people with MHO are characterized by favorable health parameters, including high insulin sensitivity, no signs of high blood pressure and less inflammation, and a healthier immune system.

There is no denying that where body fat is located is important to health, but little is known about what mechanism determines whether we are pear-shaped or apple-shaped. Under the direction of Dr. KOH Gou Young from the Center for Vascular Research at the Institute for Basic Research (IBS) in South Korea, scientists have reported about angiopoietin-2 (Angpt2) – a hormone secreted from adipose tissue and formerly known as a protein-coding peptide that is involved in embryonic vessel development is – as a key factor that inhibits the accumulation of potbellies by allowing the proper transportation of fat acid in the general circulation in blood vessels, which prevents insulin resistance. Their results were published online in the journal Nature Communications (June 12, 2020).

Angpt2 made from fat cells

Angpt2 made from adipocytes interacts with its receptor integrin α5β1 to power fatty acid transporters (CD36 and FATP3) and provides for normal circulating fat. When this Angpt2-Integrin-α5β1 signal does not work, defects in the buffering capacity of adipose tissue lead to an overflow of fat in the liver and muscle, converting brown fat into white fat and consequently leading to defects in metabolic health. Credit: IBS

“Previous approaches blocked the expression of Angpt2 throughout the circulatory system with pharmacological interventions to inhibit the accumulation of displaced fat that leads to metabolic disorders. Although the vascular endothelial cell is the anatomical and metabolic gatekeeper of fat transport in tissues, it is still uncertain whether the displaced accumulation of excess fat in adipose tissues is a cause or an indicator of metabolic syndrome. We have specifically focused on the fatty acid shuttle in the specific fatty tissues under the skin. Angpt2 plays a key role in packing fat in convenient places where it should contain a wider waist, ”says BAE Hosung, first author of this study.

The researchers found that the blood vessels under the skin contained certain fatty acid transport proteins, and compared samples from MHO and metabolically unhealthy obese people. Angpt2 turned out to be the only potential candidate for maintaining metabolic health by regulating body fat distribution. Using various tissue-specific knock-out mouse models and mechanistic studies in primarily cultured cells, they showed that Angpt2 produced from fat cells interacts with its receptor integrin α5β1 to drive fatty acid transporters and ensure a normal distribution of circulating fat. “Interestingly, the signal transmission of Angpt2 integrin α5β1 only took a few minutes. This almost instant processing makes sense, as this biological mechanism should handle the increase in fat in the blood after a meal, ”explains Bae.

Morphology and fat accumulation in the liver and muscle

Representative images of the morphology and fat accumulation in the liver (left) and muscle (right) in wild-type and adipocyte-specific Angpt2 knockout mice. Fat accumulation in adipocyte-specific Angpt2 knockout mice could be observed in white spots (top), red oil color (middle) and green fatty acid intensity (bottom). Credit: IBS

Inhibition of this process triggered fat accumulation in other fat deposits and abdominal organs, resulting in systemic glucose intolerance, reminiscent of the pattern in metabolically unhealthy obese patients.

Can Angpt2 treatment be a therapeutic strategy to normalize fat distribution and treat metabolic disorders caused by obesity? As shown in previous experiments, the systemic modulation of Angpt2 is limited by pharmacological blockade, since Angpt2 is individual and depends on the heterogeneity of different fat deposits. Alternatively, activation of integrin receptors or fatty acid transporters may be a more workable approach for their relatively restricted expression in fat cells under the skin. “More research is needed to genetically or pharmaceutically test these possibilities and to discover new therapeutic avenues for converting metabolically unhealthy obesity into healthy obesity,” added Bae.

Reference: “Angiopoietin-2-integrin-α5β1 signal transmission improves the transport of vascular fatty acids and prevents the insulin resistance induced by ectopic lipids” by Hosung Bae, Ki Yong Hong, Choong-Kun Lee, Cholsoon Jang, Seung-Jun Lee, and Kibaek Choe Stefan Offermanns, Yulong He, Hyuek Jong Lee and Gou Young Koh, June 12, 2020, Nature Communications.
DOI: 10.1038 / s41467-020-16795-4

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