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Upregulation of FGF21 to Prevent Visceral Fat Gain and Consequent Diabetes


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#1 reason

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Posted 12 July 2018 - 10:22 AM


Telling people to eat less doesn't work, as demonstrated by the vast number of overweight individuals with metabolic syndrome and type 2 diabetes. Both of those are preventable, reversible conditions, even in their later stages. All the patient has to do is eat less and lose the weight. Instead most people keep the weight, undergo largely palliative treatments that produce unpleasant side-effects, suffer many more medical complications with aging, and die younger than their peers. We don't live in a particularly rational world. Medical science may yet rescue the obese from themselves, however; certainly a very large amount of funding and effort goes into building potential treatments. Upregulation of FGF21 via gene therapy is an example of the type, a replication of one of the effects of calorie restriction that might have quite broad benefits in many organs, even for people of normal weight.

A research team has managed to cure obesity and type 2 diabetes in mice using gene therapy. A single administration of an adeno-associated viral vector (AAV) carrying the FGF21 (Fibroblast Growth Factor 21) gene, resulted in genetic manipulation of the liver, adipose tissue, or skeletal muscle to continuously produce the FGF21 protein. This protein is a hormone secreted naturally by several organs that acts on many tissues for the maintenance of correct energy metabolism. By inducing FGF21 production through gene therapy the animal lost weight and decreased insulin resistance, which causes the development of type 2 diabetes.

The therapy has been tested successfully in two different mouse models of obesity, induced either by diet or genetic mutations. In addition, the authors observed that when administered to healthy mice, the gene therapy promoted healthy ageing and prevented age-associated weight gain and insulin resistance. After treatment with AAV-FGF21, mice lost weight and reduced fat accumulation and inflammation in adipose tissue; fat content (steatosis), inflammation, and fibrosis of the liver were also reversed; this led to an increase in insulin sensitivity and in healthy ageing, without any adverse side effects.

The native FGF21 protein has a short half-life when administered using conventional procedures. For this reason, the pharmaceutical industry has developed FGF21 analogues/mimetics and has already conducted clinical trials. FGF21 analogues/mimetics, however, require periodic administration to mediate clinical benefits, but may raise immunological issues associated to the administration of exogenous proteins. The gene therapy vectors, however, induce the mice to produce for many years the same FGF21 hormone naturally produced by the body, after a single administration.

Link: https://www.eurekale...b-urc070918.php


View the full article at FightAging

#2 Darryl

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Posted 13 July 2018 - 03:55 AM

Until gene therapy is available for humans, one can also boost FGF21 through restriction of any essential amino acid, through the GCN2 > eIF2a > ATF4 > FGF21 pathway. I think this is a likely mechanism underlying metabolic benefits of the Kempner rice diet, which is at least 40% lysine deficient.

 

Laeger et al, 2014. FGF21 is an endocrine signal of protein restrictionJ clin invest124(9), pp.3913-3922.

Fazeli et al, 2015. FGF21 and the late adaptive response to starvation in humansJ clin invest125(12), pp.4601-4611.

Lees et al, 2014. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21Aging cell13(5), pp.817-827.

Laeger et al, 2016. Metabolic responses to dietary protein restriction require an increase in FGF21 that is delayed by the absence of GCN2Cell reports16(3), pp.707-716.

Gosby et al, 2016. Raised FGF-21 and triglycerides accompany increased energy intake driven by protein leverage in lean, healthy individuals: a randomised trialPloS one11(8), p.e0161003.

Hill et al, 2018. Homeostatic sensing of dietary protein restriction: A case for FGF21Front neuroendocrin.


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