Previous studies at 21 °C and 5 °C suggest that in Swiss mice sustained energy intake (SusEI) and reproductive performance are constrained by the mammary capacity to produce milk. We aimed to establish if this constraint also applied at higher ambient temperature (30 °C). Female Swiss mice lactating at 30 °C had lower asymptotic food intake and weaned lighter litters than those at 21 °C. Resting metabolic rate, daily energy expenditure, milk energy output and suckling time were all lower at 30 °C. In a second experiment we gave mice at 30 °C either 6 or 9 pups to raise. Female performance was independent of litter size, indicating that it is probably not controlled by pup demands. In a third experiment we exposed only the mother, or only the offspring to the elevated temperature. In this case the performance of the mother was only reduced when she was exposed, and not when her pups were exposed, showing that the high temperature directly constrains female performance. These data suggest that at 30 °C SusEI and reproductive performance are likely constrained by the capacity of females to dissipate body heat, and not indirectly via pup demands. Constraints seem to change with ambient temperature in this strain of mouse.

To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.

The complex and dynamic interactions between diet, gut microbiota (GM) structure and function, and colon carcinogenesis are only beginning to be elucidated. We examined the colonic microbiota and aberrant crypt foci (ACF) in C57BL/6N female mice fed various dietary interventions (control, energy restricted and high-fat) provided during two phases (initiation and progression) of azoxymethane (AOM)-induced early colon carcinogenesis. During progression (wks. 22-60), a high-fat diet enhanced ACF formation compared to a control or energy restricted diet. In contrast, energy restriction during initiation phase (wks. 3-21) enhanced ACF burden at 60 weeks, regardless of the diet in progression phase. Alterations in GM structure during the initiation phase diet were partially maintained after changing diets during the progression phase. However, diet during the progression phase had major effects on the mucosal GM. Energy restriction in the progression phase increased Firmicutes and reduced Bacteroidetes compared to a high-fat diet, regardless of initiation phase diet, suggesting that diet may have both transient effects as well as a lasting impact on GM composition. Integration of early life and adult dietary impacts on the colonic microbial structure and function with host molecular processes involved in colon carcinogenesis will be key to defining preventive strategies.

The snack food potato chips induces food intake in ad libitum fed rats, which is associated with modulation of the brain reward system and other circuits. Here, we show that food intake in satiated rats is triggered by an optimal fat/carbohydrate ratio. Like potato chips, an isocaloric fat/carbohydrate mixture influenced whole brain activity pattern of rats, affecting circuits related e.g. to reward/addiction, but the number of modulated areas and the extent of modulation was lower compared to the snack food itself.

For sustainable food production selection and breeding of feed efficient animals is crucial. The objective of this study was to evaluate whether multiparous dairy cows, ranked during their first lactation based on residual energy intake (REI) as efficient (low; L-REI) or inefficient (high; H-REI), differ in terms of nutrient use efficiency, methane emissions, rumen fermentation, and gut microbiota composition. Six L-REI and 6 H-REI cows were offered two diets with either a low or high proportion of concentrates (30 vs. 50% of DM) on two consecutive periods of 21 d. Gas exchanges, milk yield, feces and urine excretions were measured in open-circuit respiratory chambers. The results indicated that L-REI cows had higher methane yields (22.6 vs. 20.4 g/kg DM intake) and derived more energy (energy balance - 36.6 vs. - 16.9 MJ/d) and protein (N balance - 6.6 vs. 18.8 g/d) from the tissues to support similar milk yields compared to H-REI cows. Nutrient intake and digestibility were not affected by REI, and there were no interactions between REI and diet. Milk yield, milk production efficiency, and milk composition were not affected by REI except for milk urea concentration that was higher for L-REI cows (14.1 vs. 10.8 mg/100 ml). The rumen and fecal microbiota community structure and function were associated with both the diet and REI, but the diet effect was more pronounced. The current study identified several physiological mechanisms underlying the differences between high and low REI cows, but further studies are needed to distinguish the quantitative role of each mechanism.

Genome-wide association studies in the FTO gene have identified SNPs correlating with obesity and type 2 diabetes. In mice, lack of Fto function leads to intrauterine growth retardation and lean phenotype, whereas in human it is lethal. The aim of this study in a pig model was to determine the localization of the FTO protein in different tissues and cell compartments, in order to investigate potential targets of FTO action. To better understand physiological role of FTO protein, its expression was studied in pigs of different age, metabolic status and nutrition, using both microscopic methods and Western blot analysis. For the first time, FTO protein was found in vivo in the cytoplasm, of not all, but specific tissues and cells e.g. in the pancreatic β-cells. Abundant FTO protein expression was found in the cerebellum, salivary gland and kidney of adult pigs. No FTO protein expression was detected in blood, saliva, and bile, excluding its role in cell-to-cell communication. In the pancreas, FTO protein expression was positively associated with energy intake, whereas in the muscles it was strictly age-related. In IUGR piglets, FTO protein expression was much higher in the cerebellum and kidneys, as compared to normal birth body weight littermates. In conclusion, our data suggest that FTO protein may play a number of distinct, yet unknown intracellular functions due to its localization. Moreover, it may play a role in animal growth/development and metabolic state, although additional studies are necessary to clarify the detailed mechanism(s) of action.

Juvenile animals show higher energy intake (EI) per body weight (BW) to meet the energy requirements for growth. However, the underlying mechanisms that induce high EI/BW in juvenile animals remain unknown. The EI from a control diet (CD) and high fat diet (HFD), as well as BW changes were compared between juvenile (3 weeks old) and adult (8 weeks old) rats. BW gain and EI were increased in the HFD-fed adult rats compared to the CD-fed adult rats. However, in the juvenile rats, there were no differences in BW gain and EI between the CD-fed and HFD-fed groups. The locomotor activity was significantly increased in HFD group compared with the CD group in juvenile, but not in adult rats. Gamma-aminobutyric acid (GABA) neurons in the VTA were found to remain undeveloped with less GABAergic input into dopamine neurons in the juvenile rats. The deletion of the VTA GABA neurons in the adult rats significantly increased CD consumption, but showed almost no change in HFD consumption. These data suggest that undeveloped properties of VTA GABA neurons in juvenile rats can promote higher EI regardless of high or less palatable feeding, and contribute to growth promotion.

Excess weight and obesity are often associated with ectopic adipose tissue accumulation in skeletal muscles. Intermuscular adipose tissue (IMAT) impairs muscle quality and reduces insulin-stimulated skeletal muscle glucose uptake. Although energy restriction and high protein intake can decrease IMAT, the effects and mechanisms of protein intake from an energy-restricted diet on protein and fat masses in skeletal muscle have received little attention. After establishing a diet-induced overweight and obese Sprague-Dawley rat model (half male and half female), rats were divided into five groups: normal control (NC; normal weight, general maintenance diet), model control (MC; overweight and obesity, high-fat diet), energy-restricted low protein (LP; overweight and obesity, 60% energy intake of NC, general maintenance diet), energy-restricted normal protein (NP; overweight and obesity, 60% energy intake of NC, high-protein diet 1), and energy-restricted high protein (HP; overweight and obesity, 60% energy intake of NC, high-protein diet 2). After 8 weeks, plasma and skeletal muscle (quadriceps femoris and gastrocnemius) samples were collected. Plasma levels of glucose, triglycerides, and hormones were analyzed, while contents of protein, fat, and factors associated with their synthesis and degradation were evaluated in skeletal muscles. Plasma concentrations of hormones contrasted protein and fat contents in skeletal muscles. Fat weights and contents of quadriceps femoris and gastrocnemius muscles in the NP group were significantly lower compared with LP and HP groups (P < 0.05). Moreover, concentrations of factors associated with the degradation of muscle fat were significantly higher in the NP group compared with LP and HP groups (P < 0.05). During energy restriction, protein intake equal to that of a normal protein diet increased lipolysis of quadriceps femoris and gastrocnemius muscles in rats of both sexes.

The low birth weight (LBW) individual had greater risk of developing metabolic dysfunction in adulthood. The aim of this study was to test whether the LBW individual is more prone to glucose intolerance on a high nutrient dense (HND) diet, and to investigate the associated hypothalamic gene expressions using pigs as model. The intake of digestible energy intake, if calculated on a body weight basis, was greater in LBW pigs than that of normal birth weight (NBW) pigs. The LBW pigs fed the HND diet had greater digestible energy intake than those fed the NND diet at adulthood, which did not occur for NBW pigs. Notably, up-regulated hypothalamic toll-like receptor 4, interleukin 6 and phospho-NFκB p65 expressions, and the altered expressions of hypothalamic leptin receptor, suppressor of cytokine signaling 3, agouti-related protein and proopiomelanocortin predicted the overconsumption of energy intake and development of glucose intolerance in LBW pigs fed the HND diet. Collectively, pigs born with LBW had a distinct hypothalamic leptin signaling to a high nutrient dense diet, which contributed to greater energy intake and glucose intolerance.

Temperature has a profound impact on animal physiology. In this study, we examined the effect of ambient temperature on the energy stores of the model organism Drosophila melanogaster. By exposing adult males to 11 temperatures between 13 °C and 33 °C, we found that temperature significantly affects the amount of energy reserves. Whereas flies increase their fat stores at intermediate temperatures, exposure to temperatures below 15 °C or above 27 °C causes a reduction of fat reserves. Moreover, we found that glycogen stores followed a similar trend, although not so pronounced. To elucidate the underlying mechanism of these changes, we compared the temperature dependence of food consumption and metabolic rate. This analysis revealed that food intake and metabolic rate scale with temperature equally, suggesting that the temperature-induced changes in energy reserves are probably not caused by a mismatch between these two traits. Finally, we assessed the effect of temperature on starvation resistance. We found that starvation survival is a negative exponential function of temperature; however we did not find any clear evidence that implies the relative starvation resistance is compromised at non-optimal temperatures. Our results indicate that whilst optimal temperatures can promote accumulation of energy reserves, exposure to non-optimal temperatures reduces Drosophila energy stores.

Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities.

Jordan has never conducted a nutrition survey to determine nutrient and energy intakes. The current study aimed to describe the energy and macronutrient consumed by the Jordanian population. A cross-sectional food consumption study was conducted, including a sample of Jordanians using two non-consecutive 24-h dietary recalls (24-h DR) between October 2021 and March 2022. A total of 2145 males and females aged 8 to 85 years old living in households were studied. The average of two 24-h DRs for each individual was converted into energy and nutrient intakes. After measuring weight, height, and waist circumference, the body mass index (BMI) and waist-to-height ratio (WHtR) were calculated. The percentage of under-reporters was higher in women than men (58.2% vs. 45.9%). Adults and older adult women had the highest prevalence of obesity (29.6%), while adults and older adult men had the highest prevalence of overweight (41.4%). There is a significant increase in energy intake in children, boys, and all adults, compared to the recommended calories. The mean energy percentage (E %) of total fat was 38%, exceeding the upper limit of the Acceptable Macronutrient Distribution Range (AMDR). At the same time, the mean daily dietary fiber intake fell below the recommended levels (ranging from 13.5 g in children to 19.5 g in older adults). The study population consumes more fat and less fiber than the recommended levels. Actions must be taken across all age groups to correct the deviation of energy and macronutrient intakes from the recommended dietary allowances.

Diets deficient in protein often increase food consumption, body weight and fat mass; however, the underlying mechanisms remain poorly understood. We compared the effects of diets varying in protein concentrations on energy balance in obesity-prone rats. We demonstrate that protein-free (0% protein calories) diets decreased energy intake and increased energy expenditure, very low protein (5% protein) diets increased energy intake and expenditure, whereas moderately low protein (10% protein) diets increased energy intake without altering expenditure, relative to control diet (15% protein). These diet-induced alterations in energy expenditure are in part mediated through enhanced serotonergic and β-adrenergic signaling coupled with upregulation of key thermogenic markers in brown fat and skeletal muscle. The protein-free and very low protein diets decreased plasma concentrations of multiple essential amino acids, anorexigenic and metabolic hormones, but these diets increased the tissue expression and plasma concentrations of fibroblast growth factor-21. Protein-free and very low protein diets induced fatty liver, reduced energy digestibility, and decreased lean mass and body weight that persisted beyond the restriction period. In contrast, moderately low protein diets promoted gain in body weight and adiposity following the period of protein restriction. Together, our findings demonstrate that low protein diets produce divergent effects on energy balance.

Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans. Recent clinical reports have suggested that micro-deletion of the Snord116 gene cluster can lead to PWS, however, the extent of the contributions of the encoded snoRNAs is unknown. Here we show that mice lacking Snord116 globally have low birth weight, increased body weight gain, energy expenditure and hyperphagia. Consistent with this, microarray analysis of hypothalamic gene expression revealed a significant alteration in feeding related pathways that was also confirmed by in situ hybridisation. Importantly, selective deletion of Snord116 only from NPY expressing neurons mimics almost exactly the global deletion phenotype including the persistent low birth weight, increased body weight gain in early adulthood, increased energy expenditure and hyperphagia. Mechanistically, the lack of Snord116 in NPY neurons leads to the upregulation of NPY mRNA consistent with the hyperphagic phenotype and suggests a critical role of Snord116 in the control of NPY neuronal functions that might be dysregulated in PWS.

Studies in genetically modified mice establish that essential roles of endogenous neuromedin U (NMU) are anorexigenic function and metabolic regulation, indicating that NMU is expected to be a potential target for anti-obesity agents. However, in central administration experiments in rats, inconsistent results have been obtained, and the essential role of NMU energy metabolism in rats remain unclear. This study aims to elucidate the role of endogenous NMU in rats. We generated NMU knockout (KO) rats that unexpectedly showed no difference in body weight, adiposity, circulating metabolic markers, body temperature, locomotor activity, and food consumption in both normal and high fat chow feeding. Furthermore, unlike reported in mice, expressions of Nmu and NMU receptor type 2 (Nmur2) mRNA were hardly detectable in the rat hypothalamic nuclei regulating feeding and energy metabolism, including the arcuate nucleus and paraventricular nucleus, while Nmu was expressed in pars tuberalis and Nmur2 was expressed in the ependymal cell layer of the third ventricle. These results indicate that the species-specific expression pattern of Nmu and Nmur2 may allow NMU to have distinct functions across species, and that endogenous NMU does not function as an anorexigenic hormone in rats.

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/-p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/-p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/-p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/-p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/-p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/-p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.

Chronic positive energy balance has surged among societies worldwide due to increasing dietary energy intake and decreasing physical activity, a phenomenon called the energy balance transition. Here, we investigate the effects of this transition on bone mass and strength. We focus on the Indigenous peoples of New Mexico in the United States, a rare case of a group for which data can be compared between individuals living before and after the start of the transition. We show that since the transition began, bone strength in the leg has markedly decreased, even though bone mass has apparently increased. Decreased bone strength, coupled with a high prevalence of obesity, has resulted in many people today having weaker bones that must sustain excessively heavy loads, potentially heightening their risk of a bone fracture. These findings may provide insight into more widespread upward trends in bone fragility and fracture risk among societies undergoing the energy balance transition.

The increased intake of ultraprocessed foods (UPFs) in the pediatric age paralleled with the risen prevalence of childhood obesity. The Ultraprocessed Foods in Obesity (UFO) Project aimed at investigating the potential mechanisms for the effects of UPFs in facilitating pediatric obesity, focusing on the direct role of advanced glycation end-products (AGEs) on mitochondrial function, the key regulator of obesity pathophysiology. We comparatively investigated the daily dietary intake of UPFs, energy, nutrients, dietary AGEs [Nε -(carboxymethyl)lysine (CML), Nε -(1-carboxyethyl)lysine (CEL), and Nδ -(5-hydro-5- methyl-4-imidazolon-2-yl)-ornithine (MG-H1)] in 53 obese patients and in 100 healthy controls visiting the Tertiary Center for Pediatric Nutrition of the Department of Translational Medical Science at the University of Naples "Federico II". AGEs skin accumulation and mitochondrial function in peripheral blood mononuclear cells (PBMCs) were also assessed. A higher intake of UPFs and AGEs, energy, protein, fat, and saturated fatty acids was observed in obese patients. Obese children presented significantly higher skin AGEs accumulation and alterations in mitochondrial metabolism. PBMCs from healthy controls exposed to AGEs showed the same mitochondrial alterations observed in patients. These findings support the UPFs role in pediatric obesity, and the need for dietary strategies limiting UPFs exposure for obesity prevention and treatment.

Whey protein promotes weight loss and improves diabetic control, however, less is known of its bioactive components that produce such benefits. We compared the effects of normal protein (control) diet with high protein diets containing whey, or its fractions lactalbumin and lactoferrin, on energy balance and metabolism. Diet-induced obese rats were randomized to isocaloric diets: Control, Whey, Lactalbumin, Lactoferrin, or pair-fed to lactoferrin. Whey and lactalbumin produced transient hypophagia, whereas lactoferrin caused prolonged hypophagia; the hypophagia was likely due to decreased preference. Lactalbumin decreased weight and fat gain. Notably, lactoferrin produced sustained weight and fat loss, and attenuated the reduction in energy expenditure associated with calorie restriction. Lactalbumin and lactoferrin decreased plasma leptin and insulin, and lactalbumin increased peptide YY. Whey, lactalbumin and lactoferrin improved glucose clearance partly through differential upregulation of glucoregulatory transcripts in the liver and skeletal muscle. Interestingly, lactalbumin and lactoferrin decreased hepatic lipidosis partly through downregulation of lipogenic and/or upregulation of β-oxidation transcripts, and differentially modulated cecal bacterial populations. Our findings demonstrate that protein quantity and quality are important for improving energy balance. Dietary lactalbumin and lactoferrin improved energy balance and metabolism, and decreased adiposity, with the effects of lactoferrin being partly independent of caloric intake.

Fermented foods represent a significant portion of human diets with several beneficial effects. Foods produced by bacterial fermentation are enriched in short-chain fatty acids (SCFAs), which are functional products of dietary fibers via gut microbial fermentation. In addition to energy sources, SCFAs also act as signaling molecules via G-protein coupled receptors such as FFAR2 and FFAR3. Hence, dietary SCFAs in fermented foods may have a direct influence on metabolic functions. However, the detailed mechanism by dietary SCFAs remains unclear. Here, we show that dietary SCFAs protected against high-fat diet-induced obesity in mice in parallel with increased plasma SCFAs without changing cecal SCFA or gut microbial composition. Dietary SCFAs suppressed hepatic weight and lipid synthesis. These effects were abolished in FFAR3-deficient mice but not FFAR2-deficient. Thus, SCFAs supplementation improved hepatic metabolic functions via FFAR3 without influencing intestinal environment. These findings could help to promote the development of functional foods using SCFAs.