Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance

Abstract

Recent studies have demonstrated that dietary protein dilution (PD) can promote metabolic inefficiency and improve glucose metabolism. However, whether PD can promote other aspects of metabolic health, such as improve systemic lipid metabolism, and mechanisms therein remains unknown. Mouse models of obesity, such as high-fat-diet-fed C57Bl/6 N mice, and New Zealand Obese mice were fed normal (i.e., 20%P) and protein-dilute (i.e., 5%EP) diets. FGF21-/- and Cd36-/- and corresponding littermate +/+ controls were also studied to examine gene-diet interactions. Here, we show that chronic PD retards the development of hypertrigylceridemia and fatty liver in obesity and that this relies on the induction of the hepatokine fibroblast growth factor 21 (FGF21). Furthermore, PD greatly enhances systemic lipid homeostasis, the mechanisms by which include FGF21-stimulated, and cluster of differentiation 36 (CD36) mediated, fatty acid clearance by oxidative tissues, such as heart and brown adipose tissue. Taken together, our preclinical studies demonstrate a novel nutritional strategy, as well as highlight a role for FGF21-stimulated systemic lipid metabolism, in combating obesity-related dyslipidemia.

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

“…This highlights that a low Thr diet can induce many of the positive effects of dietary AA restriction while avoiding some negative side effects such as lean tissue wasting. On this, similar to that previously shown for dietary protein/AA dilution 14,16,21,49,65 , and SCAA or BCAA restriction 21,38,[42][43][44] , low Thr feeding also retarded development of obesity-induced metabolic dysfunction in a mouse model ( Fig. 5).…”

“…We previously demonstrated that dietary protein dilution (DPD) improves glucose and lipid homeostasis in obesity and that dilution of amino acids was sufficient to mimic these effects 14,16,49 . However, it remained to be resolved whether the dilution of protein by substituting with other dietary nutrients (i.e.…”

“…Dietary protein dilution (DPD) promotes metabolic health by inducing the hepatokine fibroblast growth factor 21 (FGF21) 14,16 , but the precise nutritional components driving this response are not fully defined. In particular, in order to keep total caloric supply neutral, which is an important consideration in diet-phenotype interactions 3,5 , another macronutrient source must be concomitantly increased.…”

“…DPD can also increase food intake, but particularly on low protein-high-carbohydrate diets, this increased food intake is surpassed by heightened energy expenditure, promoting a situation of systemic metabolic inefficiency 14,24 . However, on a low-protein-high-fat diet, mice gain more body weight 4,14 , which may 4 or may not 14,16 promote worsened metabolic health. This weaker response to differing diluting nutrients in DPD is perhaps due to the absence of relatively weaker satiating effects of lipids versus protein or carbohydrate 55,56 .…”

“…Unlike severe protein/AA restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies [7][8][9] , rodents 4,10,11 and perhaps humans 12 . Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related disease such as cancer 12,13 , type 2 diabetes 14,15 , and dyslipidemia/fatty liver disease 16,17 . Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans 18,19 .…”