Single ingestion of soy β-conglycinin induces increased postprandial circulating FGF21 levels exerting beneficial health effects

Hashidume, Tsutomu; Kato, Atsushi; Tanaka, Tomohiro; Miyoshi, Shoko; Itoh, Nobuyuki; Nakata, Rieko; Inoue, H.; Oikawa, Akira; Nakai, Yuji; Shimizu, Makoto; Inoue, Jun; Sato, Ryuichiro

doi:10.1038/srep28183

Cited by 45 publications

(53 citation statements)

References 44 publications

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“…To examine whether increased endogenous production of FGF21 by b-conglycinin significantly reduced postprandial ER stress, we refed mice with either normal or b-conglycinin-containing chow after overnight fasting. Consistent with a previous study (14), plasma FGF21 and hepatic FGF21 mRNA levels were greatly increased by b-conglycinin ingestion (Fig. 7A and B).…”

Section: Increased Endogenous Production Of Fgf21 By B-conglycinin Insupporting

confidence: 92%

“…For refeeding experiments using regular chow, mice were fasted overnight and refed (D12450J; Research Diet) for 3 h, then killed under anesthesia. For refeeding experiments using the b-conglycinin diet, mice were refed either chow or a b-conglycinin diet after overnight fasting, as previously described (14). The liver was rapidly excised, frozen in liquid nitrogen and stored at 280˚C until further processing.…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that ingestion of b-conglycinin, a soy protein, resulted in a marked induction of hepatic FGF21 expression via ATF4 activation (14). To examine whether increased endogenous production of FGF21 by b-conglycinin significantly reduced postprandial ER stress, we refed mice with either normal or b-conglycinin-containing chow after overnight fasting.…”

Section: Increased Endogenous Production Of Fgf21 By B-conglycinin Inmentioning

confidence: 99%

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FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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Summary Fibroblast growth factor 21 (FGF21), mainly synthesized and secreted from the liver, is an endocrine FGF that regulates glucose and fatty acid metabolism to maintain whole body energy homeostasis. Gene expression of FGF21 was previously reported to be induced by endoplasmic reticulum (ER) stress through activating transcription factor 4 (ATF4). It has been reported that drug-induced ER stress is reduced by overexpression of FGF21. However, the function of endogenous FGF21 under physiological conditions such as the postprandial state remains unknown. Here, we examined the effects of both endogenous and exogenous FGF21 on postprandial hepatic ER stress. In mice, postprandial and tunicamycin-induced ER stress was significantly reduced by overexpression of FGF21 using a recombinant adenovirus. FGF21-deficient mice exhibited a more considerable increase in drug-induced ER stress target gene expression than wild-type mice. Following refeeding after fasting, FGF21 deficiency caused severe ER stress in the liver. The postprandial ER stress response was significantly reduced when hepatic FGF21 gene expression was increased by feeding a diet containing the soy protein b-conglycinin which activates ATF4. Together, these results demonstrate that FGF21 reduces the increased expression of a subset of genes in the liver in response to ER stress and may correct metabolic disorders caused by ER stress. Key Words FGF21, ER stress, ATF4, b-conglycinin Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily (also known as the FGF19 subfamily), is mainly produced by the liver. FGF21 is secreted into the blood circulation, after which it acts on target tissues through a cell-surface FGF receptor (FGFR) together with its coregulator, bKlotho (1). In adipose tissues, FGF21 induces lipolysis and glucose uptake by activation of hormone sensitive lipase and glucose transporter 4, respectively (2, 3). Some hepatic energy metabolic pathways, including ketogenesis and gluconeogenesis, are also regulated by FGF21 in response to fasting. Expression of FGF21 is transcriptionally regulated during fasting via peroxisome proliferator-activated receptor a (PPARa), a nuclear hormone receptor (2, 4). More importantly, several studies revealed that FGF21 improves whole-body insulin sensitivity, inhibits high-fat diet-induced body weight gain and reduces fatty liver disease. Thus, FGF21 is an attractive target molecule for the prevention of metabolic diseases.Endoplasmic reticulum (ER) stress is triggered by excess accumulation of either unfolded or misfolded proteins in the ER, which in turn activates three ER membrane proteins: activating transcription factor 6a (ATF6a), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK). During ER stress, activation of PERK results in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) and translational activation of activating transcription factor 4 (ATF4). Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, red...

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Section: Increased Endogenous Production Of Fgf21 By B-conglycinin Insupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Increased Endogenous Production Of Fgf21 By B-conglycinin Inmentioning

confidence: 99%

See 1 more Smart Citation

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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“…Wistar rats that were fed with soy protein showed a reduction in adipose cell size, and elevated expression of adiponectin messenger ribonucleic acid and protein. Furthermore, β‐conglycinin in soybean has been reported to increase FGF21 levels and suppress weight gain.…”

mentioning

confidence: 99%

Associations of nutrient intakes with obesity and diabetes mellitus in the longitudinal medical surveys of Japanese Americans

Sugihiro

Yoneda

Ohno

et al. 2019

J of Diabetes Invest

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Aims/Introduction Our previous survey of two Japanese populations, with different lifestyles but identical genetic dispositions, showed that Japanese Americans had different dietary intakes and higher prevalences of obesity and diabetes mellitus, compared with the native Japanese population. The present study examined whether Westernized dietary habits could affect the development of obesity or diabetes. Materials and methods This study included 765 individuals with normal glucose tolerance at baseline medical examinations (1986 or 1989 in Los Angeles and in 1988 or 1992 in Hawaii) who subsequently completed follow‐up medical examinations several years later. The participants were categorized at baseline as “lean” (576 individuals, body mass index of <25 kg/m2) or “obese” (189 individuals, body mass index of ≥25 kg/m2). Nutrient intakes were analyzed for associations with the development of obesity or diabetes using Cox's proportional hazard model. Results A total of 41 lean participants developed diabetes, which was not associated with any nutrient intakes (mean follow up 10.8 ± 6.6 years). A total of 36 obese participants developed diabetes, which was positively associated with intakes of animal protein, animal fat and saturated fatty acid (mean follow up 10.7 ± 6.3 years). A total of 85 lean participants became obese, which was positively associated with intakes of simple carbohydrates, sugar and fructose, as well as inversely associated with intakes of vegetable protein and complex carbohydrates (mean follow up 10.4 ± 6.5 years). Conclusions In the Japanese Americans, different nutrient intakes affected the development of obesity and diabetes. Furthermore, the associations of nutrient intakes with diabetes development varied according to the presence or absence of obesity.

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“…Dietary soybean β‐conglycinin decreases serum triacylglycerol and visceral fat in slightly hyperlidemic humans (Kohno et al, ). Soybean β‐conglycinin exerts anti‐obesity effects by increasing the postprandial circulating level of FGF21 in mice (Hashidume et al, ). Soluble soybean protein peptic hydrolysate stimulates adipocyte differentiation, with concomitant increase in adiponectin mRNA expression, adiponectin secretion, and PPAR‐gamma expression in 3T3‐L1 cells (Goto, Mori, & Nagaoka, ).…”

Section: Anti‐obesity Action Of Peptidementioning

confidence: 99%

Structure-function properties of hypolipidemic peptides

Nagaoka

2018

J Food Biochem

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This review addresses the structure-function properties of hypolipidemic peptides. The cholesterol-lowering peptide (lactostatin: IIAEK) operates via a new regulatory pathway in the calcium-channel-related mitogen-activated protein kinase (MAPK) signaling pathway of cholesterol degradation. The bile acid binding peptide (soystatin, VAWWMY) inhibits the micellar solubility of cholesterol in vitro and cholesterol absorption in vivo. VVYP is the most effective peptide having hypotriglyceridemic action in globin digests. The suppressive effect of globin digest on postprandial hyperlipidemia has been reported in humans. The ability of peptides (KRES, Apolipoprotein A-I mimetic peptides) to interact with lipids, remove LOOH and activate antioxidant enzymes associated with high-density lipoprotein determines their anti-inflammatory and anti-atherogenic properties. The b-conglycinin derived peptides KNPQLR, EITPEKNPQLR, and RKQEEDEDEE QQRE inhibit fatty acid synthase in vitro. These promising findings indicate the need for more conclusive molecular, cellular, and animal and human studies to design innovative new peptides that ameliorate cholesterol and lipid metabolism. Practical applicationsPrevention and amelioration of hypercholesterolemia by dietary regulation are important. Dietary protein and peptides are very useful as regulators of serum cholesterol concentration. Diets low in saturated fat and cholesterol that include soy protein may reduce the risk of heart disease. In Japan, the concept of "food for specified health use" has been introduced for the prevention and treatment of life-style related disease. Thus, peptides derived from food proteins and sources other than food proteins such as peptide-rich functional foods and nutraceutical products, have considerable potential to prevent lifestyle-related diseases, especially hyperlipidemia, as discussed in this review. Furthermore, various strategies have been used for the efficient screening, development, and application of new hypolipidemic peptides. These include the use of phage display (for antiobesity peptide), peptide mimetics (for anti-atherogenic peptide), and molecular targets such as CYP7A1 (for hypocholesterolemic peptide) and prohibitin (for anti-obesity peptide).

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Single ingestion of soy β-conglycinin induces increased postprandial circulating FGF21 levels exerting beneficial health effects

Cited by 45 publications

References 44 publications

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Associations of nutrient intakes with obesity and diabetes mellitus in the longitudinal medical surveys of Japanese Americans

Structure-function properties of hypolipidemic peptides

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