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Dietary choices have a profound impact on the aging process. In addition to the total amount of energy intake, macronutrient composition influences both health and lifespan. However, the exact mechanisms by which dietary macronutrients influence onset and progression of age-associated features remain poorly understood. Cellular senescence is a state of stable growth arrest characterized by the secretion of numerous bioactive molecules with pro-inflammatory properties. Accumulation of senescent cells is considered one of the basic mechanisms of aging and an important contributor to chronic inflammation and tissue degeneration. Whether dietary macronutrients affect the accumulation and the phenotype of senescent cells with age is still unknown. Here, we show that feeding on diets with varying ratios of dietary macronutrients for 3 months has a significant effect on different senescence-associated markers in the mouse liver. High protein intake is associated with higher expression levels of the two classical senescence-associated growth arrest genes, p21 and p16. Furthermore, the expression of many pro-inflammatory secretory markers was increased in diets enriched in protein and further enhanced by increases in fat content. These results provide preliminary evidence that dietary macronutrients have a significant influence on senescence markers and merit further investigation.

Dietary macronutrient composition influences both hepatic function and aging. Previous work suggested that longevity and hepatic gene expression levels were highly responsive to dietary protein, but almost unaffected by other macronutrients. In contrast, we found expression of 4005, 4232, and 4292 genes in the livers of mice were significantly associated with changes in dietary protein (5%-30%), fat (20%-60%), and carbohydrate (10%-75%), respectively. More genes in aging-related pathways (notably mTOR, IGF-1, and NF-kappaB) had significant correlations with dietary fat intake than protein and carbohydrate intake, and the pattern of gene expression changes in relation to dietary fat intake was in the opposite direction to the effect of graded levels of caloric restriction consistent with dietary fat having a negative impact on aging. We found 732, 808, and 995 serum metabolites were significantly correlated with dietary protein (5%-30%), fat (8.3%-80%), and carbohydrate (10%-80%) contents, respectively. Metabolomics pathway analysis revealed sphingosine-1-phosphate signaling was the significantly affected pathway by dietary fat content which has also been identified as significant changed metabolic pathway in the previous caloric restriction study. Our results suggest dietary fat has major impact on aging-related gene and metabolic pathways compared with other macronutrients.

A variety of inbred mouse strains have been used for research in metabolic disorders. Despite being inbred, they display large inter-individual variability for many traits like food intake and body weight. However, the relationship between dietary macronutrients and inter-individual variation in body weight and food intake of different mouse strains is still unclear. We investigated the association between macronutrient content of the diet and variations in food intake, body composition, and glucose tolerance by exposing five different mouse strains (C57BL/6, BALB/c, C3H, DBA/2, and FVB) to 24 different diets with variable protein, fat, and carbohydrate contents. We found only increasing dietary fat, but not protein or carbohydrate had a significant association (positive) with variation in both food intake and body weight. The highest variation in both body weight and food intake occurred with 50% dietary fat. However, there were no significant relationships between the variation in fat and lean mass with dietary protein, fat, or carbohydrate levels. In addition, none of the dietary macronutrients had significant impacts on the variation in glucose tolerance ability in C57BL/6 mice. In conclusion, the variations in food intake and body weight changes increased with the elevation of dietary fat levels.

Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis., Nature Communications, 12 (1), ISSN:2041-1723

Objective Maternal high-fat diet (HFD) increases offspring obesity, yet the impacts of different levels of maternal dietary fat have seldom been addressed. In mice, the impact of graded maternal dietary fat on offspring adiposity and offspring's later susceptibility to HFD were assessed. Methods Lactating mice were fed diets with graded fat content from 8.3% to 66.6%. One male and one female pup from each litter were weaned onto a low-fat diet for 15 weeks. HFD (41.7%) was then introduced to half of the offspring for 12 weeks. Results Offspring body weight and adiposity were positively related to maternal dietary fat content and were higher when mothers were exposed to HFD. The maternal diet effect was nonlinear and sex dependent. A maternal dietary fat of 41.7% and above exaggerated the offspring body weight gain in males but was not significant in females. Maternal 8.3% fat and 25% fat diets led to the highest daily energy expenditure and respiratory exchange ratio in offspring. Offspring fed a low-fat diet had higher daily energy expenditure and respiratory exchange ratio than those fed an HFD. Conclusions Increasing maternal dietary fat during lactation, and HFD in later life, had significant and interacting impacts on offspring obesity. Maternal diet had a bigger impact on male offspring. The effects of maternal dietary fat content were nonlinear.

As a major health issue, obesity is linked with elevated risk of type 2 diabetes. However, whether disrupted glucose homeostasis is due to altered body composition alone, or whether dietary macronutrients play an additional role, independent of their impact on body composition, remains unclear. We investigated the associations between macronutrients, body composition, blood hormones and glucose homeostasis. We fed C57BL/6N mice 29 different diets with variable macronutrients for 12 weeks. After 10 weeks, intraperitoneal glucose tolerance tests were performed. Generalized linear models were generated to evaluate the impacts of macronutrients, body composition and blood hormones on glucose homeostasis. The area under the glucose curve (AUC) was strongly associated with body fat mass, but not dietary macronutrients. AUC was significantly associated with fasting insulin levels. Six genes from transcriptomic analysis of epididymal white adipose tissue and subcutaneous white adipose tissue were significantly associated with AUC. These genes may encode secreted proteins that play important previously unanticipated roles in glucose homeostasis., Hu et al. found that disrupted glucose homeostasis in obese mice is mainly due to high body fatness, and dietary fat plays an additional role on fasting glucose levels.

Objectives The carbohydrate-insulin model (CIM) predicts that increases in fasting and post-prandial insulin in response to dietary carbohydrates stimulate energy intake and lower energy expenditures, leading to positive energy balance and weight gain. The objective of the present study was to directly test the CIM's predictions using C57BL/6 mice. Methods Diets were designed by altering dietary carbohydrates with either fixed protein or fat content and were fed to C57BL/6 mice acutely or chronically for 12 weeks. The body weight, body composition, food intake, and energy expenditures of the mice were measured. Their fasting and post-prandial glucose and insulin levels were also measured. RNA-seq was performed on RNA from the hypothalamus and subcutaneous white adipose tissue. Pathway analysis was conducted using IPA. Results Only the post-prandial insulin and fasting glucose levels followed the CIM's predictions. The lipolysis and leptin signaling pathways in the sWAT were inhibited in relation to the elevated fasting insulin, supporting the CIM's predicted impact of high insulin. However, because higher fasting insulin was unrelated to carbohydrate intake, the overall pattern did not support the model. Moreover, the hypothalamic hunger pathways were inhibited in relation to the increased fasting insulin, and the energy intake was not increased. The browning pathway in the sWAT was inhibited at higher insulin levels, but the daily energy expenditure was not altered. Conclusions Two of the predictions were partially supported (and hence also partially not supported) and the other three predictions were not supported. We conclude that the CIM does not explain the impact of dietary macronutrients on adiposity in mice., Highlights • Higher fasting insulin related to inhibited lipolysis and leptin pathways in sWAT, supporting CIM. • Higher fasting insulin related to inhibited hypothalamic hunger pathway, contrasting CIM. • Fasting insulin decreased with higher dietary carbohydrate, overall contrasting CIM. • Higher dietary carbohydrate did not lead to greater EI/adiposity, or lowered EE.

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.

The impacts of different macronutrients on body weight regulation remain unresolved, with different studies suggesting increased dietary fat, increased carbohydrates (particularly sugars), or reduced protein may all stimulate overconsumption and drive obesity. We exposed C57BL/6 mice to 29 different diets varying from 8.3% to 80% fat, 10% to 80% carbohydrate, 5% to 30% protein, and 5% to 30% sucrose. Only increased dietary fat content was associated with elevated energy intake and adiposity. This response was associated with increased gene expression in the 5-HT receptors, and the dopamine and opioid signaling pathways in the hypothalamus. We replicated the core findings in four other mouse strains (DBA/2, BALB/c, FVB, and C3H). Mice regulate their food consumption primarily to meet an energy rather than a protein target, but this system can be over-ridden by hedonic factors linked to fat, but not sucrose, consumption.

Synaptic connections must be precisely controlled to ensure proper neural circuit formation. In Drosophila melanogaster, bone morphogenetic protein (BMP) promotes growth of the neuromuscular junction (NMJ) by binding and activating the BMP ligand receptors wishful thinking (Wit) and thickveins (Tkv) expressed in motor neurons. We report here that an evolutionally conserved, previously uncharacterized member of the S6 kinase (S6K) family S6K like (S6KL) acts as a negative regulator of BMP signaling. S6KL null mutants were viable and fertile but exhibited more satellite boutons, fewer and larger synaptic vesicles, larger spontaneous miniature excitatory junctional potential (mEJP) amplitudes, and reduced synaptic endocytosis at the NMJ terminals. Reducing the gene dose by half of tkv in S6KL mutant background reversed the NMJ overgrowth phenotype. The NMJ phenotypes of S6KL mutants were accompanied by an elevated level of Tkv protein and phosphorylated Mad, an effector of the BMP signaling pathway, in the nervous system. In addition, Tkv physically interacted with S6KL in cultured S2 cells. Furthermore, knockdown of S6KL enhanced Tkv expression, while S6KL overexpression downregulated Tkv in cultured S2 cells. This latter effect was blocked by the proteasome inhibitor MG132. Our results together demonstrate for the first time that S6KL regulates synaptic development and function by facilitating proteasomal degradation of the BMP receptor Tkv., Author Summary Bi-directional signaling between neurons and their target cells is critical for synapse formation, growth, and plasticity, as well as for neuronal survival. Bone morphogenetic protein (BMP) acts as a retrograde signal promoting synaptic growth at the Drosophila neuromuscular junction (NMJ), but little is known about proteins that regulate BMP signaling by controlling BMP release, receptor expression, and signal transduction. We report here that a previously uncharacterized and evolutionally conserved member of the S6 kinase (S6K) family S6K like (S6KL) inhibits BMP signaling by interacting with and promoting proteasome-mediated degradation of the BMP receptor Thickveins (Tkv). In S6KL mutants, there was an elevated level of Tkv protein, together with overgrown NMJs characterized by excess satellite boutons. Reducing the gene dose of tkv by half in S6KL null background restored normal NMJ morphology, suggesting that S6KL normally serves to suppress Tkv-mediated BMP signaling. Biochemically, S6KL interacted with Tkv. Overexpression of S6KL down-regulated Tkv and this effect was inhibited by blocking the proteasomal degradation pathway. Collectively, our data demonstrate that S6KL regulates NMJ synapse development by promoting the proteasomal degradation of Tkv. Thus, we have identified a novel negative regulator of BMP signaling in the Drosophila nervous system.

Stand-alone electronic equipments are important parts of a satellite system, inside which remainders will bring great harm to reliability of the satellite system. Particle shock noise detection (PIND) is an effective method to detect the remainders in stand-alone electronic equipments. Signal to noise ratio (SNR) of detection signal is a bottleneck to improve processing accuracy and robustness of testing software. In this paper, key factors of wavelet threshold de-noising method were investigated and a wavelet threshold algorithm was proposed to improve the SNR of remainder detection signal of the stand-alone electronic equipments. The analytic results proved that the wavelet threshold method efficiently improved the de-noising effect.