Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation.

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment.

Chronic sleep fragmentation reduces left ventricular contractile function and alters gene expression related to innate immune response and circadian rhythm in the mouse heart.

Sleep disorders have emerged as a widespread public health concern, primarily due to their association with an increased risk of developing cardiovascular diseases. Our previous research indicated a potential direct impact of insufficient sleep duration on cardiac remodeling in children and adolescents. Nevertheless, the underlying mechanisms behind the link between sleep fragmentation (SF) and cardiac abnormalities remain unclear. In this study, we aimed to investigate the effects of SF interventions at various life stages on cardiac structure and function, as well as to identify genes associated with SF-induced cardiac dysfunction. To achieve this, we established mouse models of chronic SF and two-week sleep recovery (SR). Our results revealed that chronic SF significantly compromised left ventricular contractile function across different life stages, leading to alterations in cardiac structure and ventricular remodeling, particularly during early life stages. Moreover, microarray analysis of mouse heart tissue identified two significant modules and nine hub genes (Ddx60, Irf9, Oasl2, Rnf213, Cmpk2, Stat2, Parp14, Gbp3, and Herc6) through protein-protein interaction analysis. Notably, the interactome predominantly involved innate immune responses. Importantly, all hub genes lost significance following SR. The second module primarily consisted of circadian clock genes, and real-time PCR validation demonstrated significant upregulation of Arntl, Dbp, and Cry1 after SF, while subsequent SR restored normal Arntl expression. Furthermore, the expression levels of four hub genes (Ddx60, Irf9, Oasl2, and Cmpk2) and three circadian clock genes (Arntl, Dbp, and Cry1) exhibited correlations with structural and functional echocardiographic parameters. Overall, our findings suggest that SF impairs left ventricular contractile function and ventricular remodeling during early life stages, and this may be mediated by modulation of the innate immune response and circadian rhythm. Importantly, our findings suggest that a short period of SR can alleviate the detrimental effects of SF on the cardiac immune response, while the influence of SF on circadian rhythm appears to be more persistent. These findings underscore the importance of good sleep for maintaining cardiac health, particularly during early life stages.

Links between energy budgets, somatic condition, and life history reveal heterogeneous energy management tactics in a group-living mesocarnivore.

BACKGROUND: Optimal management of voluntary energy expenditure is crucial to the survival and reproductive success of wild animals. Nevertheless, a growing appreciation of inter-individual variation in the internal state driving movement suggests that individuals may follow different, yet equally optimal tactics under the same environmental conditions. However, few studies in wild populations have investigated the occurrence and demographic context of different contemporaneous energetic expenditure tactics. Here, we explore this neglected aspect of energy budgeting in order to determine the effect of life-history traits such as age and reproductive status on the co-occurrence of different energy-budgeting tactics in wild populations. METHODS: We investigated inter-individual heterogeneity in energy expenditure within a wild population of European badgers (Meles meles) by quantifying individual overall dynamic body acceleration (ODBA, from tri-axial accelerometry collars) and total daily energy expenditure (DEE, from doubly-labelled water) during 6-9 day deployments and dosing periods over six different seasons (spring, summer, and autumn) in 2018-2019. We obtained ODBA values for 41 deployments (24 unique badgers) and DEE measurements for 41 dosings (22 unique badgers). We then evaluated correlations between these energetic metrics and computed individual ratios of ODBA/DEE as a proxy for the proportion of total energy spent on activity. We measured the impact of alternative ODBA/DEE ratios on body condition, and use survival models constructed using 29 years of demographic data from the same population to situate body-condition changes in the context of age and reproductive status. RESULTS: Both ODBA and DEE were highly variable between individuals and exhibited season-specific relationships with individual body condition and life-history factors. DEE scaled allometrically with body weight, but only in summer and autumn; post-reproductive female badgers were lighter than other badgers during the spring but expended on average 350 kJ/day more than predicted from allometric scaling. Older badgers expended significantly less energy on movement during the summer than did younger adults. The ratio of ODBA to DEE (OD) provides a measure of proportional investment into movement. This ratio correlated more significantly with next-season body condition than either energetic metric did independently. However, the majority of individuals with high OD ratios were either younger badgers or reproductive females, for which lower body condition typically presented less of a mortality risk in previous analyses of this population. CONCLUSIONS: Within a single population under the same environmental conditions, we found wide inter-individual variation in both mechanical and total energy expenditure. The adoption of different tactics aligns with relationships between life-history parameters and mortality risk previously studied within the population. Crucially, younger badgers and reproductive females appeared able to tolerate energy expenditure tactics that depleted their body condition more than other badgers. These findings provide a mechanism by which differences in individual energetic context set by life history can maintain heterogeneity in wild populations, providing a wide range of potential energetic tactics under changing environmental conditions.

Maternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice.

Maternal overnutrition during lactation predisposes offspring to develop metabolic diseases and exacerbates the relevant syndromes in males more than females in later life. The hypothalamus is a heterogenous brain region that regulates energy balance. Here we combined metabolic trait quantification of mother and offspring mice under low and high fat diet (HFD) feeding during lactation, with single nucleus transcriptomic profiling of their offspring hypothalamus at peak lacation to understand the cellular and molecular alterations in response to maternal dietary pertubation. We found significant expansion in neuronal subpopulations including histaminergic (Hdc), arginine vasopressin/retinoic acid receptor-related orphan receptor ß (Avp/Rorb) and agouti-related peptide/neuropeptide Y (AgRP/Npy) in male offspring when their mothers were fed HFD, and increased Npy-astrocyte interactions in offspring responding to maternal overnutrition. Our study provides a comprehensive offspring hypothalamus map at the peak lactation and reveals how the cellular subpopulations respond to maternal dietary fat in a sex-specific manner during development.

The hedonic overdrive model best explains high-fat diet-induced obesity in C57BL/6 mice.

OBJECTIVE: High-fat diets cause obesity in male mice; however, the underlying mechanisms remain controversial. Here, three contrasting ideas were assessed: hedonic overdrive, reverse causality, and passive overconsumption models. METHODS: A total of 12 groups of 20 individually housed 12-week-old C57BL/6 male mice were exposed to 12 high-fat diets with varying fat content from 40% to 80% (by calories), protein content from 5% to 30%, and carbohydrate content from 8.4% to 40%. Body weight and food intake were monitored for 30 days after 7 days at baseline on a standard low-fat diet. RESULTS: After exposure to the diets, energy intake increased first, and body weight followed later. Intake then declined. The peak energy intake was dependent on both dietary protein and carbohydrate, but not the dietary fat and energy density, whereas the rate of decrease in intake was only related to dietary protein. On high-fat diets, the weight of food intake declined, but despite this average reduction of 14.4 g in food intake, they consumed, on average, 357 kJ more energy than at baseline. CONCLUSIONS: The hedonic overdrive model fit the data best. The other two models were not supported.

Limits to sustained energy intake. XXXIV. Can the heat dissipation limit (HDL) theory explain reproductive aging?

According to the heat dissipation limit (HDL) theory, reproductive performance is limited by the capacity to dissipate excess heat. We tested the novel hypotheses that (1) the age-related decline in reproductive performance is due to an age-related decrease of heat dissipation capacity and (2) the limiting mechanism is more severe in animals with high metabolic rates. We used bank voles (Myodes glareolus) from lines selected for high swim-induced aerobic metabolic rate, which have also increased basal metabolic rate, and unselected control lines. Adult females from three age classes - young (4 months), middle-aged (9 months) and old (16 months) - were maintained at room temperature (20°C), and half of the lactating females were shaved to increase heat dissipation capacity. Old females from both selection lines had a decreased litter size, mass and growth rate. The peak-lactation average daily metabolic rate was higher in shaved than in unshaved mothers, and this difference was more profound among old than young and middle-aged voles (P=0.02). In females with large litters, milk production tended to be higher in shaved (least squares mean, LSM±s.e.: 73.0±4.74 kJ day-1) than in unshaved voles (61.8±4.78 kJ day-1; P=0.05), but there was no significan"t effect of fur removal on the growth rate [4.47±2.29 g (4 days-1); P=0.45]. The results provide mixed support of the HDL theory and no support for the hypotheses linking the differences in reproductive aging with either a deterioration in thermoregulatory capability or genetically based differences in metabolic rate.

Validation of predictive equations to estimate resting metabolic rate of females and males across different activity levels.

OBJECTIVES: Using equations to predict resting metabolic rate (RMR) has yielded different degrees of validity, particularly when sex and different physical activity levels were considered. Therefore, the purpose of the present study was to determine the validity of several different predictive equations to estimate RMR in female and male adults with varying physical activity levels. METHOD: We measured the RMR of 50 adults (26 females and 24 males) evenly distributed through activity levels varying from sedentary to ultra-endurance. Body composition was measured by dual X-ray absorptiometry and physical activity was monitored by accelerometry. Ten equations to predict RMR were applied (using Body Mass [BM]: Harris & Benedict, 1919; Mifflin et al., 1990 [MifflinBM]; Pontzer et al., 2021 [PontzerBM]; Schofield, 1985; FAO/WHO/UNU, 2004; and using Fat-Free Mass (FFM): Cunningham, 1991; Johnstone et al., 2006; Mifflin et al., 1990 [MifflinFFM]; Nelson et al. 1992; Pontzer et al., 2021 [PontzerFFM]). The accuracy of these equations was analyzed, and the effect of sex and physical activity was evaluated using different accuracy metrics. RESULTS: Equations using BM were less accurate for females, and their accuracy was influenced by physical activity and body composition. FFM equations were slightly less accurate for males but there was no obvious effect of physical activity or other sample parameters. PontzerFFM provides higher accuracy than other models independent of the magnitude of RMR, sex, activity levels, and sample characteristics. CONCLUSION: Equations using FFM were more accurate than BM equations in our sample. Future studies are needed to test the accuracy of RMR prediction equations in diverse samples.

Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms.

Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA, particularly in younger individuals. Metabolic abnormalities, such as obesity and type II diabetes, are strongly linked to OA, and they affect both weight-bearing and non-weight-bearing joints, thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight. This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk, including the impact of abnormal glucose and lipid metabolism, the potential pathogenesis and targeted therapeutic strategies.

Determining energy expenditure in a large seabird using accelerometry.

The trade off between energy gained and expended is the foundation of understanding how, why and when animals perform any activity. Based on the concept that animal movements have an energetic cost, accelerometry is increasingly being used to estimate energy expenditure. However, validation of accelerometry as an accurate proxy for field metabolic rate in free-ranging species is limited. In the present study, Australasian gannets (Morus serrator) from the Pope's Eye colony (38°16'42″S 144°41'48″E), south-eastern Australia, were equipped with GPS and tri-axial accelerometers and dosed with doubly labelled water (DLW) to measure energy expenditure during normal behaviour for 3-5 days. The correlation between daily energy expenditure from the DLW and vectorial dynamic body acceleration (VeDBA) was high for both a simple correlation and activity-specific approaches (R2=0.75 and 0.80, respectively). Varying degrees of success were observed for estimating at-sea metabolic rate from accelerometry when removing time on land using published energy expenditure constants (R2=0.02) or activity-specific approaches (R2=0.42). The predictive capacity of energy expenditure models for total and at-sea periods was improved by the addition of total distance travelled and proportion of the sampling period spent at sea during the night, respectively (R2=0.61-0.82). These results indicate that accelerometry can be used to estimate daily energy expenditure in free-ranging gannets and its accuracy may depend on the inclusion of movement parameters not detected by accelerometry.

Phylogenetic signal in gut microbial community rather than in rodent metabolic traits.

Host phylogeny and environment have all been implicated in shaping the gut microbiota and host metabolic traits of mammals. However, few studies have evaluated phylogeny-associated microbial assembly and host metabolic plasticity concurrently, and their relationships on both short-term and evolutionary timescales. We report that the branching order of a gut microbial dendrogram was nearly congruent with phylogenetic relationships of seven rodent species, and this pattern of phylosymbiosis was intact after diverse laboratory manipulations. Laboratory rearing, diet or air temperature (Ta) acclimation induced alterations in gut microbial communities, but could not override host phylogeny in shaping microbial community assembly. A simulative heatwave reduced core microbiota diversity by 26% in these species, and led to an unmatched relationship between the microbiota and host metabolic phenotypes in desert species. Moreover, the similarity of metabolic traits across species at different Tas was not correlated with phylogenetic distance. These data demonstrated that the gut microbial assembly showed strong concordance with host phylogeny and may be shaped by environmental variables, whereas host metabolic traits did not seem to be linked with phylogeny.

Great tits (Parus major) in a west European temperate forest show little seasonal variation in metabolic energy requirements.

Understanding how birds annually allocate energy to cope with changing environmental conditions and physiological states is a crucial question in avian ecology. There are several hypotheses to explain species' energy allocation. One prominent hypothesis suggests higher energy expenditure in winter due to increased thermoregulatory costs. The "reallocation" hypothesis suggests no net difference in seasonal energy requirements, while the "increased demand" hypothesis predicts higher energy requirements during the breeding season. Birds are expected to adjust their mass and/or metabolic intensity in ways that are consistent with their energy requirements. Here, we look for metabolic signatures of seasonal variation in energy requirements of a resident passerine of a temperate-zone (great tit, Parus major). To do so, we measured whole-body and mass-independent basal (BMR), summit (Msum), and field (FMR) metabolic rates during late winter and during breeding in Belgian great tits. During the breeding season, birds had on average 10% higher whole-body BMR and FMR compared to winter, while their Msum decreased by 7% from winter to breeding. Mass-independent metabolic rates showed a 10% increase in BMR and a 7% decrease in Msum from winter to breeding. Whole-body BMR was correlated with Msum, but this relationship did not hold for mass-independent metabolic rates. The modest seasonal change we observed suggests that great tits in our temperature study area maintain a largely stable energy budget throughout the year, which appears mostly consistent with the reallocation hypothesis.

Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.

Early life nutrition can reprogram development and exert long-term consequences on body weight regulation. In mice, maternal high-fat diet (HFD) during lactation predisposed male but not female offspring to diet-induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex-differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro-opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex-dependent susceptibility to obesity in adult life in mice.

Daily energy requirements of male academy soccer players are greater than age-matched non-academy soccer players: A doubly labelled water investigation.

This study aimed to test the hypothesis that the total daily energy expenditure (TDEE) of male academy soccer players is greater than players not enrolled on a formalised academy programme. English Premier League academy (ACAD: n = 8, 13 years, 50 ± 6 kg, 88 ± 3% predicted adult stature, PAS) and non-academy players (NON-ACAD: n = 6, 13 years, 53 ± 12 kg, 89 ± 3% PAS) were assessed for TDEE (via doubly labelled water) during a 14-day in-season period. External loading was evaluated during training (ACAD: 8 sessions, NON-ACAD: 2 sessions) and games (2 games for both ACAD and NON-ACAD) via GPS, and daily physical activity was evaluated using triaxial accelerometry. Accumulative duration of soccer activity (ACAD: 975 ± 23 min, NON-ACAD: 397 ± 2 min; p < 0.01), distance covered (ACAD: 54.2 ± 8.3 km, NON-ACAD: 21.6 ± 4.7 km; p < 0.05) and time engaged in daily moderate-to-vigorous (ACAD: 124 ± 17 min, NON-ACAD: 79 ± 18 min; p < 0.01) activity was greater in academy players. Academy players displayed greater absolute (ACAD: 3380 ± 517 kcal · d-1, NON-ACAD: 2641 ± 308 kcal · d-1; p < 0.05) and relative TDEE (ACAD: 66 ± 6 kcal · kg · d-1, NON-ACAD: 52 ± 10 kcal · kg · d-1; p < 0.05) versus non-academy players. Given the injury risk associated with high training volumes during growth and maturation, data demonstrate the requirement for academy players to consume sufficient energy (and carbohydrate) intake to support the enhanced energy cost of academy programmes.

Limits to sustained energy intake. XXXIII. Thyroid hormones play important roles in milk production but do not define the heat dissipation limit in Swiss mice.

The limits to sustained energy intake set physiological upper boundaries that affect many aspects of human and animal performance. The mechanisms underlying these limits, however, remain unclear. We exposed Swiss mice to either supplementary thyroid hormones (THs) or the inhibitor methimazole during lactation at 21 or 32.5°C, and measured food intake, resting metabolic rate (RMR), milk energy output (MEO), serum THs and mammary gland gene expression of females, and litter size and mass of their offspring. Lactating females developed hyperthyroidism following exposure to supplementary THs at 21°C, but they did not significantly change body temperature, asymptotic food intake, RMR or MEO, and litter and mass were unaffected. Hypothyroidism, induced by either methimazole or 32.5°C exposure, significantly decreased asymptotic food intake, RMR and MEO, resulting in significantly decreased litter size and litter mass. Furthermore, gene expression of key genes in the mammary gland was significantly decreased by either methimazole or heat exposure, including gene expression of THs and prolactin receptors, and Stat5a and Stat5b. This suggests that endogenous THs are necessary to maintain sustained energy intake and MEO. Suppression of the thyroid axis seems to be an essential aspect of the mechanism by which mice at 32.5°C reduce their lactation performance to avoid overheating. However, THs do not define the upper limit to sustained energy intake and MEO at peak lactation at 21°C. Another, as yet unknown, factor prevents supplementary thyroxine exerting any stimulatory metabolic impacts on lactating mice at 21°C.

Models of body weight and fatness regulation.

Body weight and fatness appear to be regulated phenomena. Several different theoretical models are available to capture the essence of this idea. These include the set-point, dynamic equilibrium, adiposity force, control theory-settling point, Hall-Guo, operation point and dual intervention point (DIP) models. The set-point model posits a single reference point around which levels of fat are regulated. The dynamic equilibrium model suggests that the apparent regulation of body fat around a reference point is an illusion owing to the necessary impacts of weight change on energy expenditure. Control theory focuses on the importance of feedback gain and suggests set-point and dynamic equilibrium are ends of a continuum of feedback gain. Control theory models have also been called 'settling point' models. The Hall-Guo, operation point and DIP models also bring together the set-point and dynamic equilibrium ideas into a single framework. The DIP proposes a zone of indifference where dynamic equilibrium 'regulation' predominates, bounded by upper and lower intervention points beyond which physiological mechanisms are activated. The drifty gene hypothesis is an idea explaining where this individual variation in the upper intervention point might come from. We conclude that further experiments to test between the models are sorely required. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

A step toward precision gerontology: Lifespan effects of calorie and protein restriction are consistent with predicted impacts on entropy generation.

Understanding aging is a key biological goal. Precision gerontology aims to predict how long individuals will live under different treatment scenarios. Calorie and protein restriction (CR and PR) extend lifespan in many species. Using data from C57BL/6 male mice under graded CR or PR, we introduce a computational thermodynamic model for entropy generation, which predicted the impact of the manipulations on lifespan. Daily entropy generation decreased significantly with increasing CR level, but not PR. Our predictions indicated the lifespan of CR mice should increase by 13 to 56% with 10 to 40% CR, relative to ad libitum-fed animals. This prediction was broadly consistent with the empirical observation of the lifespan impacts of CR in rodents. Modeling entropy fluxes may be a future strategy to identify antiaging interventions.

Unanswered questions about the causes of obesity.

Obesity is now a global pandemic, but there is little consensus about the causes.

Chowing down: diet considerations in rodent models of metabolic disease.

Diet plays a substantial role in the etiology, progression, and treatment of chronic disease and is best considered as a multifaceted set of modifiable input variables with pleiotropic effects on a variety of biological pathways spanning multiple organ systems. This brief review discusses key issues related to the design and conduct of diet interventions in rodent models of metabolic disease and their implications for interpreting experiments. We also make specific recommendations to improve rodent diet studies to help better understand the role of diet on metabolic physiology and thereby improve our understanding of metabolic disease.

Quantifying physical activity energy expenditure based on doubly labelled water and basal metabolism calorimetry: what are we actually measuring?

PURPOSE OF REVIEW: Physical activity impacts energy balance because of its contribution to total energy expenditure. Measuring physical activity energy expenditure (PAEE) is often performed by subtracting the estimated 24 h expenditure on basal metabolism (called basal energy expenditure or BEE) from the total energy expenditure (TEE) measured by doubly labelled water minus an estimate of the thermic effect of food (TEF). Alternatively it can be measured as the ratio of TEE/BEE, which is commonly called the physical activity level (PAL). RECENT FINDINGS: PAEE and PAL are widely used in the literature but their shortcomings are seldom addressed. In this review, we outline some of the issues with their use. SUMMARY: TEE and BEE are both measured with error. The estimate of PAEE by difference magnifies these errors and consequently the precision of estimated PAEE is about 3× worse than TEE and 25-35× worse than BEE. A second problem is that the component called PAEE is actually any component of TEE that is not BEE. We highlight how the diurnal variation of BEE, thermoregulatory expenditure and elevations of RMR because of stress will all be part of what is called PAEE and will contribute to a disconnect between what is measured and what energy expenditure is a consequence of physical activity. We emphasize caution should be exerted when interpreting these measurements of PAEE and PAL.