A form of the metabolic syndrome associated with mutations in DYRK1B.

BACKGROUND: Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. METHODS: We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. RESULTS: A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family. CONCLUSIONS: These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.).

Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6(R611C) mutation and phenotypically characterized their liver. Homozygote LRP6(R611C) (LRP6(mut/mut)) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-α/-µ pathways. Accordingly, there was increased TGF-ß1 activity, coupled with enhanced expression of smooth muscle α-actin and vimentin that colocalized with albumin in LRP6(mut/mut) mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6(mut/mut) mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH.

Effect of mechanically deboned chicken meat hydrolysates on the physicochemical properties of imitation fish paste.

This study investigated on the effects of adding mechanically deboned chicken meat (MDCM) hydrolysates on the quality properties of imitation fish paste (IFP) during storage. IFP was prepared from Alaska Pollack, spent laying hens surimi and protein hydrolysates which were enzymatically extracted from MDCM. The study was designed as a 3×4 factorial design with three MDCM hydrolysate content groups (0%, 0.4%, and 0.8%) and four storage times (0, 2, 4, and 6 weeks). Addition of MDCM hydrolysates increased crude fat content but lowered water content (p<0.05). The breaking force of IFP, an indicator of gel formation, increased in treated groups compared to control (p<0.05). Angiotensin I-converting enzyme (ACE) activity was inhibited and free radical scavenging activity increased with increasing MDCM hydrolysate content (p<0.05). In conclusion, the addition of MDCM to IFP improves gel characteristics. Additionally, protein hydrolysates from MDCM serve as a potential source of ACE inhibiting peptides.

Black beans (Glycine max (L.) Merrill) included in a multi-grain rice reduce total cholesterol and enhance antioxidant capacity in high-fat diet-induced obese mice.

This study investigated the effects of black bean (BB) supplementation on the growth performance, lipid metabolism, and antioxidant capacity of high-fat diet-induced obese mice. The results demonstrated that although the inclusion of BBs led to increased body weight, total energy intake, and feed efficiency ratio, it did not significantly alter the overall body composition, including adiposity. Notably, BB consumption reduced total cholesterol levels, suggesting its potential to manage dyslipidemia and reduce the risk of atherosclerotic cardiovascular diseases. Furthermore, BBs significantly enhanced in the total antioxidant capacity, as indicated by the notable increase in both the total antioxidant capacity and superoxide dismutase activity. These findings provide significant insights into the promising health benefits of BBs in the context of metabolic syndrome and related health complications.

Exploring the multifaceted role of ginkgolides and bilobalide from Ginkgo biloba in mitigating metabolic disorders.

The ancient Ginkgo biloba tree grows across various regions, with distinctive leaves emitting a unique fragrance. Its extract contains flavonoids, organic acids, and terpenoids. Ginkgolide and bilobalide, which are G. biloba leaf extracts, offer diverse pharmaceutical benefits, including antioxidant, anti-inflammatory, and neuroprotective properties. The antioxidant and anti-inflammatory properties of these compounds are crucial for mitigating neurodegeneration, particularly in diseases such as Alzheimer's disease. Additionally, their effectiveness in countering oxidative stress and inflammation highlights their potential to prevent cardiovascular ailments. This study also suggests that these compounds have a promising impact on lipid metabolism, suggesting their significance in addressing obesity-related metabolic disorders. In conclusion, ginkgolides and bilobalide exhibit promising effects in sustaining the integrity of the nervous and endocrine systems, along with the modulation of lipid metabolism. The diverse health benefits suggest that these compounds could serve as promising therapeutic interventions for various conditions, including neurological, cardiovascular, and metabolic diseases.

Ambivalence towards pork belly: exploring its significance and contradictions from the perspectives of the food industry and nutritional science.

Pork is the most consumed meat in South Korea, and pork belly is the preferred cut. However, pork production cannot meet the demand, leading to a heavy reliance on imports, particularly for pork bellies. In contrast, low-fat cuts face oversupply problems owing to low demand and export challenges. Pork belly fat content varies with breed, sex, growth rate, and fatty acid composition. Western countries favor higher fat saturation for processed products, whereas South Koreans prefer grilled or roasted bellies. Excessive consumption of high-fat pork cuts like pork belly, which is rich in saturated fatty acids, can increase the risk of severe diseases, highlighting the importance of reducing saturated fat intake and increasing the consumption of monounsaturated fatty acids and polyunsaturated fatty acids to mitigate these risks. The pork industry and public health sector should diversify production, promote leaner pork, and raise awareness about the implications of excessive pork consumption.

The Herbal Blend of Sphaeranthus indicus and Garcinia mangostana Reduces Adiposity in High-Fat Diet Obese Mice.

Obesity is swiftly becoming a global epidemic, leading to numerous metabolic disorders and substantial socio-economic burdens. Investigating natural bioactive compounds is crucial to support the use of traditional anti-obesity medications while mitigating the adverse effects. This study posited that a combination of Sphaeranthus indicus and Garcinia mangostana (Meratrim) could prevent fat accumulation in obese mice. We used 4-week-old C57BL/6NTac mice, dividing them into six groups: (1) normal diet (ND); (2) high-fat diet (HFD, 45% kcal from fat); (3-5) Meratrim150, Meratrim300, and Meratrim450 (HFD with 150, 300, and 450 mg/kg bw of Meratrim); and (6) Metformin (HFD with 150 mg/kg bw of metformin). Meratrim was administered orally each day for 20 weeks. The group receiving 450 mg/kg of Meratrim showed a significant reduction in body weight and fat mass without changes in food consumption. The Meratrim450 group had markedly lower triglyceride levels in both serum and liver. Importantly, Meratrim-supplemented mice improved lipid homeostasis by inhibiting hepatic de novo lipogenesis and activating energy catabolic pathways such as non-shivering thermogenesis in brown adipose tissue. Our results suggest that the herbal mixture of Sphaeranthus indicus and Garcinia mangostana (Meratrim) is a promising natural anti-obesity agent, owing to its efficacy in reducing body fat and enhancing lipid homeostasis.

Alleviation of Menopausal Symptoms by Yam (Dioscorea japonica Thunb.) and Gromwell (Lithospermum erythrorhizon Sieb. Et Zucc.) Extracts in Ovariectomized Mice.

SCOPE: The decline in estrogen during menopause contributes to a variety of menopausal symptoms, for which hormone replacement therapy (HRT) has been extensively applied. Regarding side effects and limited effectiveness of HRT for specific individuals, there is a growing interest in safe alternatives such as phytoestrogens which are structurally analogous to estrogens. This study aims to investigate the efficacy of yam and gromwell extracts, rich in bioactive compounds, and the synergistic effect of extracts on symptoms induced by estrogen deficiency in ovariectomized (OVX) mice. METHODS AND RESULTS: OVX mice receive dietary intervention of either yam, gromwell extract, or their mixture for 14 weeks. Sham-operated mice and E2-injected OVX mice serve as positive controls. Following 14 weeks of oral administration, blood, adipose tissue, vagina, uterus, femurs, and tibias are harvested for further investigation. Consequently, yam and gromwell extracts ameliorate menopausal conditions such as weight gain, glucose intolerance, dyslipidemia, and osteoporosis in estrogen-deficient OVX mice. In addition, the mixture of yam and gromwell extracts synergistically aids in the relief of the indications. CONCLUSION: These results indicate the potential use of yam and gromwell extracts, as well as their mixture, for the development of healthy functional foods to modulate menopausal symptoms.

Effect of MIND diet on cognitive function in elderly: a narrative review with emphasis on bioactive food ingredients.

As the world becomes a super-aged society, cognitive decline is public health problems that are increasing rapidly. A healthy diet has great potential for maintaining cognitive health. A diet that could delay the onset of neurodegenerative diseases has been developed: the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, a hybrid form of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. In this review, the effects of the MIND diet on improving cognitive function, including memory, are summarized. In most studies, the higher the adherence to the MIND diet, the higher the cognitive function evaluation score, and the lower the incidence of dementia. This is because of the anti-inflammatory and antioxidant effects of the major nutritional components of the MIND diet: folate, carotenoids, polyphenols, and polyunsaturated fatty acids. Adherence to the MIND diet, containing various bioactive food ingredients, is related to cognitive improvement in the elderly population.

Correction to: A combined extract containing Schisandra chinensis (SCE) reduced hepatic triglyceride accumulation in rats fed a high­sucrose diet.

[This corrects the article DOI: 10.1007/s10068-023-01464-1.].

A combined extract containing Schisandra chinensis (SCE) reduced hepatic triglyceride accumulation in rats fed a high-sucrose diet.

Excessive hepatic lipid accumulation is closely linked to inflammation, insulin resistance, and metabolic syndromes. We hypothesized that a combined extract containing Schisandra chinensis (SCE) could alleviate hepatic lipid accumulation. Male Sprague-Dawley rats fed a high-sucrose diet (HSD) were randomly assigned to three groups (n = 6): normal diet (ND), HSD (60% kcal from sucrose), and HSD + SCE (HSD with 2.44% SCE). Liquid chromatography-tandem mass spectrometry revealed that SCE contains chlorogenic acid (5.514 ± 0.009 mg/g) and schisandrin (0.179 ± 0.002 mg/g) as bioactive components. SCE did not alter the body weight, fat mass, lean mass, or glucose levels. Strikingly, SCE effectively reduced the plasma triglyceride (TG) and hepatic TG levels compared to the HSD group. Adiposity reduction is due to decreased activity of hepatic de novo lipogenic enzymes. These results indicated that SCE has nutraceutical potential for the prevention and treatment of hepatic steatosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01464-1.

Rare nonconservative LRP6 mutations are associated with metabolic syndrome.

A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

LRP6 protein regulates low density lipoprotein (LDL) receptor-mediated LDL uptake.

Genetic variations in LRP6 gene are associated with high serum LDL cholesterol levels. We have previously shown that LDL clearance in peripheral B-lymphocytes of the LRP6(R611C) mutation carriers is significantly impaired. In this study we have examined the role of wild type LRP6 (LRP6(WT)) and LRP6(R611C) in LDL receptor (LDLR)-mediated LDL uptake. LDL binding and uptake were increased when LRP6(WT) was overexpressed and modestly reduced when it was knocked down in LDLR-deficient CHO (ldlA7) cells. These findings implicated LRP6 in LDLR-independent cellular LDL binding and uptake. However, LRP6 knockdown in wild type CHO cells resulted in a much greater decline in LDL binding and uptake compared with CHO-ldlA7 cells, suggesting impaired function of the LDLR. LDLR internalization was severely diminished when LRP6 was knocked down and was restored after LRP6 was reintroduced. Further analysis revealed that LRP6(WT) forms a complex with LDLR, clathrin, and ARH and undergoes a clathrin-mediated internalization after stimulation with LDL. LDLR and LRP6 internalizations as well as LDL uptake were all impaired in CHO-k1 cells expressing LRP6(R611C). These studies identify LRP6 as a critical modulator of receptor-mediated LDL endocytosis and introduce a mechanism by which variation in LRP6 may contribute to high serum LDL levels.

Possible involvement of Mycoplasma hominis in inhibiting the formation of biofilms by uropathogenic Escherichia coli (UPEC).

Here we examined the involvement of Mycoplasma hominis in the formation of biofilms by uropathogenic Escherichia coli (UPEC) strain CFT073. Initially, we thought that M. hominis does not affect the fitness of UPEC, including the growth and production of signaling molecules, such as autoinducer-2 and indole. We found, however, that the presence of M. hominis significantly decreased the degree of biofilm formation by UPEC CFT073 (approximately a 60% reduction for 10(5) ccu/mL of M. hominis as compared with UPEC alone). We also found that it had a slight effect in inhibiting the attachment and cytotoxicity of UPEC CFT073. These findings are specific to these UPEC strains rather than to enterohemorrhagic E. coli (EHEC) strains, found in normal intestinal flora. In addition, we performed whole-transcriptome profiling and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. This indicated that the PhoPQ system and the anti-termination protein (encoded by ybcQ) were involved in the reduction of biofilm formation by M. hominis (corroborated by qRT-PCR). Furthermore, our results indicate that M. hominis raises the degree of transcription of toxin genes, including hha and pasT. Hence, we suggest a possible role of M. hominis in affecting the formation of biofilms by UPEC in the urinary tract.

Rottlerin suppresses lipid accumulation by inhibiting de novo lipogenesis and adipogenesis via LRP6/mTOR/SREBP1C in 3T3-L1 adipocytes.

Rottlerin is isolated from Mallotus japonicus, a plant rich in polyphenols. Rottlerin is a selective PKCδ-inhibitor and is also known as an uncoupler of oxidative phosphorylation and anti-neoplastic agent. However, its anti-obesity effect is yet to be established. Therefore, this study tested whether rottlerin inhibits adipogenesis and de novo lipogenesis via the LRP6/mTOR/SREBP1C pathway in 3T3-L1 adipocytes. Rottlerin dramatically decreased lipid accumulation assessed by Oil Red O as evidence to support the cellular phenotype (p < 0.001). Pivotal messenger RNA and protein expressions associated with de novo lipogenesis (SREBP1C, ACC1, FAS, and SCD1) and adipogenesis (PPARγ and C/EBPα) were subsequentially verified by rottlerin in a dose-dependent manner (p < 0.05). Further investigation revealed that rottlerin reduced the AKT/mTOR pathway via diminished total protein of LRP6 (p < 0.05). Collectively, these findings establish a causal link between rottlerin, LRP6, and the altered nutrient-sensing mTOR pathway, in which rottlerin regulates de novo lipogenesis and adipogenesis in white adipocytes.

Recent Advances in Nutraceuticals for the Treatment of Sarcopenic Obesity.

Sarcopenic obesity, low muscle mass, and high body fat are growing health concerns in the aging population. This review highlights the need for standardized criteria and explores nutraceuticals as potential therapeutic agents. Sarcopenic obesity is associated with insulin resistance, inflammation, hormonal changes, and reduced physical activity. These factors lead to impaired muscle activity, intramuscular fat accumulation, and reduced protein synthesis, resulting in muscle catabolism and increased fat mass. Myostatin and irisin are myokines that regulate muscle synthesis and energy expenditure, respectively. Nutritional supplementation with vitamin D and calcium is recommended for increasing muscle mass and reducing body fat content. Testosterone therapy decreases fat mass and improves muscle strength. Vitamin K, specifically menaquinone-4 (MK-4), improves mitochondrial function and reduces muscle damage. Irisin is a hormone secreted during exercise that enhances oxidative metabolism, prevents insulin resistance and obesity, and improves bone quality. Low-glycemic-index diets and green cardamom are potential methods for managing sarcopenic obesity. In conclusion, along with exercise and dietary support, nutraceuticals, such as vitamin D, calcium, vitamin K, and natural agonists of irisin or testosterone, can serve as promising future therapeutic alternatives.

Blended extract of oat, sorghum, adzuki bean, finger millet, and proso millet improved hyperglycemia and insulin resistance in the streptozotocin-nicotinamide-induced diabetic rats.

Grains contain bioactive components that potentially have protective effects on chronic diseases such as diabetes. The anti-diabetic effects of blended grain ethanol extract (BGE) were evaluated in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats. BGE was prepared by mixing oat, sorghum, adzuki bean, finger millet, and proso millet (30:30:15:15:10). The rats were assigned into four groups, normal control, diabetic model control (DM), STZ-NA rats administered 200 mg/kg body weight (bw) of metformin, and STZ-NA rats administered 500 mg/kg bw of BGE (BGE). After 6 weeks of administration, the homeostatic model assessment of insulin resistance (12%) in BGE decreased compared to DM. Strikingly, the fasting blood glucose (23%) and oral glucose tolerance test (15%) were improved in BGE compared to DM. BGE also increased insulin immunoreactivities in pancreatic ß-cells. In sum, BGE exhibits anti-hyperglycemic effects by improving fasting glucose levels and insulin secretion from pancreatic ß-cells in the STZ-NA-induced diabetic rats.

Comparison of the effects of commercial whey protein and native whey protein on muscle strength and muscle protein synthesis in rats.

Commercial whey protein (CWP) is generally produced in the cheese making process with heat treatment. Recently, native whey protein (NWP) can be obtained through microfiltration without heat treatment. The difference in physicochemical properties of CWP and NWP was confirmed in previous studies; however, in vivo research on the effect on muscle strength and protein synthesis is still lacking. In this study, rats were orally administered 1.56 g protein/kg body weight of lyophilized beverages containing CWP and NWP for 8 weeks. The biological value and net protein utilization in the NWP were significantly higher than in the CWP. Moreover, NWP increased muscle mass and grip strength compared to CWP. NWP also increased the phosphorylation of the mammalian target of rapamycin and ribosomal protein S6 kinase, pivotal proteins for muscle protein synthesis. These results suggest that NWP enhance muscle strength and protein synthesis more effectively than CWP.

Comparison of physicochemical properties of sorghum extract by ethanol concentration and its anti-adipogenic effect in 3T3-L1 cells.

Sorghum is a vital cereal source that has various phenolic compounds and potential health-promoting benefits. This study evaluated the phenolic content, antioxidant and anti-obesity effects of sorghum extract (SE) prepared using three solvent systems: 50% (SE50), 80% (SE80), and 100% (SE100) ethanol. The results showed that SE50 exhibited the highest total polyphenol and flavonoid content among the sorghum extracts using different ethanol concentrations as extraction solvents. In addition, SE50 showed significantly higher antioxidant capacity than the other extracts. Interestingly, SE50 significantly inhibited lipid accumulation in 3T3-L1 adipocytes; however, SE80 and SE100 had no beneficial effects. Moreover, SE50 significantly downregulated the mRNA expression levels of adipogenic genes (Cebpα, Pparγ, and Fabp4) and lipogenic genes (Srebp1c, Fas, and Scd1). These results suggest that SE50 is superior to other ethanol extracts in phenolic contents, antioxidant and anti-obesity activities, and it could be used as a nutraceutical for anti-obesity.

Modified Korean MIND Diet: A Nutritional Intervention for Improved Cognitive Function in Elderly Women through Mitochondrial Respiration, Inflammation Suppression, and Amino Acid Metabolism Regulation.

SCOPE: Mild cognitive impairment is associated with a high prevalence of dementia. The study examines the benefits of a modified Korean MIND (K-MIND) diet and explores biomarkers using multi-omics analysis. METHODS AND RESULTS: The K-MIND diet, tailored to the elderly Korean population, includes perilla oil, milk, or fermented milk, and avoids alcohol consumption. As a result, the K-MIND diet significantly improves subjects "orientation to place" in the Korean version of the Mini-Mental State Examination, 2nd edition test. According to multi-omics analysis, the K-MIND diet upregulates genes associated with mitochondrial respiration, including ubiquinone oxidoreductase, cytochrome C oxidase, and ATP synthase, and immune system processes, and downregulates genes related to nuclear factor kappa B activity and inflammatory responses. In addition, K-MIND affects the metabolic pathways of glycine, serine, threonine, tryptophan, and sphingolipids, which are closely linked to cognitive function through synthesis of neurotransmitters and structures of brain cell membranes. CONCLUSION: The findings imply that the K-MIND diet improves cognitive function by upregulating key genes involved in oxidative phosphorylation and downregulating pro-inflammatory cytokines.