Fibroblast growth factor 21 (FGF21) is the first known endocrine signal activated by protein restriction. Although FGF21 is robustly elevated in low-protein environments, increased FGF21 is also seen ...in various other contexts such as fasting, overfeeding, ketogenic diets, and high-carbohydrate diets, leaving its nutritional context and physiological role unresolved and controversial. Here, we use the Geometric Framework, a nutritional modeling platform, to help reconcile these apparently conflicting findings in mice confined to one of 25 diets that varied in protein, carbohydrate, and fat content. We show that FGF21 was elevated under low protein intakes and maximally when low protein was coupled with high carbohydrate intakes. Our results explain how elevation of FGF21 occurs both under starvation and hyperphagia, and show that the metabolic outcomes associated with elevated FGF21 depend on the nutritional context, differing according to whether the animal is in a state of under- or overfeeding.
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•FGF21 is maximally elevated under low protein, high carbohydrate intakes•The Geometric Framework reconciles conflicting findings on FGF21 elevation•Metabolic effects of FGF21 are dependent on nutrient context
FGF21 is elevated in seemingly opposite nutrient contexts such as starvation, overfeeding, protein restriction, and ketogenic and high-carbohydrate diets. Using the Geometric Framework and 25 different types of diets, Solon-Biet et al. reconcile these findings and demonstrate that maximal FGF21 elevation occurs on low protein, high carbohydrate intakes.
The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, ...findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models-the diacylglycerol (DAG) model and the ceramide model-have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are ...beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
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•Calorie restriction (CR) and low-protein, high-carb (LPHC) diets improve health•Hippocampus RNA expression is positively influenced by CR and LPHC diets•Nutrient-sensing pathways are similarly influenced by CR and LPHC diets•CR and LPHC diets positively influence dendritic spines and cognitive function
Calorie restriction (CR) and ad libitum low-protein, high-carbohydrate (LPHC) diets improve cardiometabolic health in mice. Wahl et al. show that, like healthspan, CR and LPHC diets positively affect hippocampus biology in mice by influencing hippocampus gene expression, nutrient-sensing pathways, dendritic morphology, and cognition.
Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when ...dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA
or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.
Obesity is a serious public health issue worldwide. Growing evidence demonstrates the efficacy of the ketogenic diet (KD) for weight loss, but there may be some adverse side effects such as ...dyslipidemia and hepatic steatosis. Aerobic exercise is a widely recognized approach for improving these metabolic markers. Here we explored the combined impacts of KD and moderate aerobic exercise for an 8-week intervention on body weight and fat loss, serum biomarkers, and hepatic lipid metabolism in a mouse model of high-fat diet-induced obesity. Both KD and KD combined with exercise significantly reduced body weight and fat mass. No significant adverse effects of KD were observed in serum biomarkers or hepatic lipid storage, except for an increase in circulating triglyceride level. However, aerobic exercise lowered serum triglyceride levels, and further ameliorated serum parameters, and hepatic steatosis in KD-fed mice. Moreover, gene and protein expression analysis indicated that KD combined with exercise was associated with increased expression of lipolysis-related genes and protein levels, and reduced expression of lipogenic genes relative to KD without exercise. Overall, our findings for mice indicate that further work on humans might reveal that KD combined with moderate aerobic exercise could be a promising therapeutic strategy for obesity.
The metabolic effects of sugars and fat lie at the heart of the "carbohydrate vs fat" debate on the global obesity epidemic. Here, we use nutritional geometry to systematically investigate the ...interaction between dietary fat and the major monosaccharides, fructose and glucose, and their impact on body composition and metabolic health. Male mice (n = 245) are maintained on one of 18 isocaloric diets for 18-19 weeks and their metabolic status is assessed through in vivo procedures and by in vitro assays involving harvested tissue samples. We find that in the setting of low and medium dietary fat content, a 50:50 mixture of fructose and glucose (similar to high-fructose corn syrup) is more obesogenic and metabolically adverse than when either monosaccharide is consumed alone. With increasing dietary fat content, the effects of dietary sugar composition on metabolic status become less pronounced. Moreover, higher fat intake is more harmful for glucose tolerance and insulin sensitivity irrespective of the sugar mix consumed. The type of fat consumed (soy oil vs lard) does not modify these outcomes. Our work shows that both dietary fat and sugars can lead to adverse metabolic outcomes, depending on the dietary context. This study shows how the principles of the two seemingly conflicting models of obesity (the "energy balance model" and the "carbohydrate insulin model") can be valid, and it will help in progressing towards a unified model of obesity. The main limitations of this study include the use of male mice of a single strain, and not testing the metabolic effects of fructose intake via sugary drinks, which are strongly linked to human obesity.
Abstract
Carbohydrates are the major source of dietary energy, but their role in health and disease remains controversial. Recent epidemiological evidence suggests that the increased consumption of ...carbohydrates is associated with obesity and increased risk of mortality and dietary trials show that carbohydrate restriction leads to weight loss and improved glycaemic status in obese and diabetic subjects. In contrast, the diets of populations with long and healthy lifespans (e.g. traditional Okinawans from Japan) are high in carbohydrate and low in protein, and several clinical and preclinical studies have linked low-carbohydrate–high-protein diets with increased mortality risk. In this paper we attempt to reconcile these contradictory findings by moving beyond traditional single-nutrient analyses to consider the interactions between nutrients on health outcomes. We do so using the Geometric Framework (GF), a nutritional modelling platform that explicitly considers the main and interactive effects of multiple nutrients on phenotypic characteristics. Analysis of human data by GF shows that weight loss and improved cardio-metabolic outcomes under carbohydrate restriction derive at least in part from reduced caloric intake due to the concomitantly increased proportion of protein in the diet. This is because, as in many animals, a specific appetite for protein is a major driver of food intake in humans. Conversely, dilution of protein in the diet leverages excess food intake through compensatory feeding for protein (‘protein leverage’). When protein is diluted in the diet by readily digestible carbohydrates and fats, as is the case in modern ultra-processed foods, protein leverage results in excess calorie intake, leading to rising levels of obesity and metabolic disease. However, when protein is diluted in the diet by increased quantities of less readily digestible forms of carbohydrate and fibre, energy balance is maintained and health benefits accrue, especially during middle age and early late-life. We argue that other controversies in carbohydrate research can be resolved using the GF methodology in dietary studies.
Abstract
Aims
The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis.
...Methods and results
Plasma TMAO increased in mice on ‘unhealthy’ high-choline diets and notably also on ‘healthy’ high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE−/− and Ldlr−/− mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage.
Conclusions
Dietary-induced changes in the microbiome, of both ‘healthy’ and ‘unhealthy’ diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk.
Graphical Abstract
Consumption of dietary macronutrients is associated with the progression of a wide range of inflammatory diseases, either by direct modulation of host immune response or via microbiome. This includes ...periodontitis, a disease affecting tooth-supporting tissues.
The aim of this work was to systematically review studies focusing on the effect of macronutrient (ie, carbohydrate, protein, fat) intake on periodontitis in rodents.
Electronic searches were performed in February 2021 using the PubMed and Web of Science databases. Out of 883 articles reviewed, 23 studies were selected for additional analysis.
Investigators extracted relevant data, including author names; the year of publication; article title; macronutrient composition; number and species of animals and their age at the start of the experiment; intervention period; method of periodontitis induction; and primary and secondary periodontitis outcomes. Quality assessment was done using the risk-of-bias tool for animal studies. After completing the data extraction, descriptive statistical information was obtained.
High intakes of dietary cholesterol, saturated fatty acids, and processed carbohydrates such as sucrose, and protein-deficient diets were positively associated with periodontitis in rodents. This included greater amounts of alveolar bone loss, more lesions on periodontal tissues, and dental plaque accumulation. In contrast, high doses of milk basic protein in diets and diets with a high ratio of ω-3 to ω-6 fatty acids were negatively associated with periodontitis in rodents.
This work highlights the fact that, despite the large body of evidence linking macronutrients with inflammation and ageing, overall there is little information on how dietary nutrients affect periodontitis in animal models. In addition, there is inconsistency in data due to differences in methodology, outcome measurement, and dietary formulation. More studies are needed to examine the effects of different dietary macronutrients on periodontitis and investigate the underlying biological mechanisms.
Nutrient sensing pathways influence metabolic health and aging, offering the possibility that diet might be used therapeutically, alone or with drugs targeting these pathways. We used the Geometric ...Framework for Nutrition to study interactive and comparative effects of diet and drugs on the hepatic proteome in mice across 40 dietary treatments differing in macronutrient ratios, energy density, and drug treatment (metformin, rapamycin, resveratrol). There was a strong negative correlation between dietary energy and the spliceosome and a strong positive correlation between dietary protein and mitochondria, generating oxidative stress at high protein intake. Metformin, rapamycin, and resveratrol had lesser effects than and dampened responses to diet. Rapamycin and metformin reduced mitochondrial responses to dietary protein while the effects of carbohydrates and fat were downregulated by resveratrol. Dietary composition has a powerful impact on the hepatic proteome, not just on metabolic pathways but fundamental processes such as mitochondrial function and RNA splicing.
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•Dietary energy intake has a negative correlation with abundance of spliceosome proteins•Protein intake correlates with abundance of mitochondrial proteins and oxidative stress•Metformin, rapamycin, and resveratrol dampen responses to nutrients•Abundance of SLC25A51, the mitochondrial NAD transporter increased with protein intake
In a study of the hepatic proteome, Le Couteur et al. show that dietary energy and macronutrients influence fundamental cellular machinery, including the spliceosome and mitochondria. Metformin, rapamycin, and resveratrol broadly dampened the proteomic responses to diet rather than acting on specific nutrient sensing pathways. The impact of diet was substantially more significant than that of drugs.
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