Disturbances In Energy Balance Research Articles

Long-term priming of hypothalamic microglia is associated with energy balance disturbances under diet-induced obesity.

Exposure of microglia to an inflammatory environment may lead to their priming and exacerbated response to future inflammatory stimuli. Here we aimed to explore hypothalamic microglia priming and its consequences on energy balance regulation. A model of intracerebroventricular administration of neuraminidase (NA, which is present in various pathogens such as influenza virus) was used to induce acute neuroinflammation. Evidences of primed microglia were observed 3 months after NA injection, namely (1) a heightened response of microglia located in the hypothalamic arcuate nucleus after an in vivo inflammatory challenge (high fat diet [HFD] feeding for 10 days), and (2) an enhanced response of microglia isolated from NA‐treated mice and challenged in vitro to LPS. On the other hand, the consequences of a previous NA‐induced neuroinflammation were further evaluated in an alternative inflammatory and hypercaloric scenario, such as the obesity generated by continued HDF feeding. Compared with sham‐injected mice, NA‐treated mice showed increased food intake and, surprisingly, reduced body weight. Besides, NA‐treated mice had enhanced microgliosis (evidenced by increased number and reactive morphology of microglia) and a reduced population of POMC neurons in the basal hypothalamus. Thus, a single acute neuroinflammatory event may elicit a sustained state of priming in microglial cells, and in particular those located in the hypothalamus, with consequences in hypothalamic cytoarchitecture and its regulatory function upon nutritional challenges.

Prolonged Activation of Brain CB2 Signaling Modulates Hypothalamic Microgliosis and Astrogliosis in High Fat Diet-Fed Mice.

Low-grade inflammation of the hypothalamus is associated with the disturbance of energy balance. The endocannabinoid system has been implicated in the development and maintenance of obesity as well as in the control of immune responses. The type 2 cannabinoid receptor (CB2) signaling has been associated with anti-inflammatory effects. Therefore, in high fat diet (HFD)-induced obese mice, we modulated CB2 signaling and investigated its effects on energy homeostasis and hypothalamic microgliosis/astrogliosis. We observed no effect on caloric intake and body weight gain in control diet-fed animals that received prolonged icv infusion of the CB2 receptor agonist HU308. Interestingly, we observed a decrease in glucose tolerance in HFD-fed animals treated with HU308. Prolonged icv infusion of HU308 increases astrogliosis in the ventromedial nucleus (VMH) of obese animals and reduced HFD-induced microgliosis in the hypothalamic arcuate (ARC) but not in the paraventricular (PVN) or VMH nuclei. These data indicate that central CB2 signaling modulates glucose homeostasis and glial reactivity in obesogenic conditions, irrespective of changes in body weight.

The Thermodynamic Consequences of Parkinson's Disease.

Several lines of evidence point to a pervasive disturbance of energy balance in Parkinson's disease (PD). Weight loss, common and multifactorial, is the most observable sign of this. Bradykinesia may be best understood as an underinvestment of energy in voluntary movement. This accords with rodent experiments that emphasise the importance of dopamine in allocating motor energy expenditure. Oxygen consumption studies in PD suggest that, when activities are standardised for work performed, these inappropriate energy thrift settings are actually wasteful. That the dopaminergic deficit of PD creates a problem with energy efficiency highlights the role played by the basal ganglia, and by dopamine, in thermodynamic governance. This involves more than balancing energy, since living things maintain their internal order by controlling transformations of energy, resisting probabilistic trends to more random states. This review will also look at recent research in PD on the analysis of entropy—an information theory metric of predictability in a message—in recordings from the basal ganglia. Close relationships between energy and information converge around the concept of entropy. This is especially relevant to the motor system, which regulates energy exchange with the outside world through its flow of information. The malignant syndrome in PD, a counterpart of neuroleptic malignant syndrome, demonstrates how much thermodynamic disruption can result from breakdown of motor signalling in an extreme hypodopaminergic state. The macroenergetic disturbances of PD are consistent with a unifying hypothesis of dopamine's neurotransmitter actions—to adapt energy expenditure to prevailing economic circumstances.

Effect of heat stress on the values of biochemical blood parameters of dairy cattle

The aim of the study was to determine the effect of heat stress on differences between selected biochemical blood parameters in cows in June and October, taking into account different housing systems and cooling systems used. The research was carried out on 60 cows from stanchion barns (farm A) and loose-house barns (farm B). Material for research, venous blood, was collected at the same time, in the morning, after milking and clinical examination. Then, parameters describing the energy balance and the activity indexes of the parenchymal organs as well as the mineral balance were determined. Milk production in both farms was clearly lower in June than in October, but the difference between milk yields obtained from the two farms was over 15% in June and only less than 10% (5-6 kg of milk) in October. Both farms A and B showed an increase in aspartate aminotransferase and creatine kinase. In farm A, the statistically significant increase exceeded the normal physiological range, which could indicate developing disturbances in the locomotor system caused by the impact of high temperature. Energy balance disturbances occurred only in farm A, where a statistically significant decrease in glucose and cholesterol concentration was found in June samples, which, according to the authors, could be related to a higher energy demand. The results of biochemical tests of venous blood collected in June may indicate the onset of fatty liver in cows (decreased cholesterol, glucose, and total protein levels, as well as increased bilirubin levels and GGTP activity) as a consequence of exposure to high temperatures. Heat stress has a significant impact on the functioning of the cow’s organism, which will not always be manifested by characteristic clinical signs. Accurate laboratory analyses make it possible to diagnose changes developing as a result of cows being exposed to heat stress.

GDF15 Induces Anorexia through Nausea and Emesis

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and hasbecome a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry.

Abstract 5066: Chemoprevention of breast cancer by targeting glucose metabolism with HJC0152

Abstract Most mammalian cells use glucose as the primary fuel source, which is metabolized via glycolysis to pyruvate and further transferred into mitochondria for generating ATP through the Krebs cycle under normal condition. However, metabolism is characteristically reprogrammed in cancer cells or highly proliferative cells with a preferential ATP production through generating lactate by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, while disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) is activated downstream of many cytokines and growth factor receptors. STAT3-targeting genes and their functions vary depending on the cellular context, primarily in correlation with cell survival and proliferation. Recently, reports show that active STAT3 with phosphorylation at Y705 residue plays an important role in regulating energy metabolism via transcriptional induction of its well-recognized transcriptional target HIF-1α. HJC0152, a novel small-molecule glucose metabolism modulator, was proprietarily developed using a combination approach of structure-based drug design strategies and molecular modeling techniques in our attempt to develop orally bioavailable non-peptide STAT3 inhibitors for anticancer use. A panel of mammary epithelial cells and breast cancer cells treated with HJC0152 exhibited suppressed cell growth and induced apoptosis in vitro. Intriguingly, HJC0152 reduces glucose uptake and Glut1 protein level. In addition, HJC0152 treated BC cell line showed decreased protein level of glycolytic enzymes including HK2, PFKL, ALDOA, PDHK, PKM2, LDHA and important metabolism regulator HIF-1α in a time-dependent manner. Furthermore, HJC0152 has significant in vivo efficacy in reducing/preventing mammary tumor development in transgenic mouse models of estrogen receptor (ER)-negative breast cancer. These results provide a rationale to develop HJC0152 as a promising drug candidate and preventive therapy for breast cancer and other cancers with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors driving the development of breast cancer in the context of metabolic dysregulation and diseases. This work was supported by grant R01CA226001 from the NIH/NCI. Citation Format: Hyejin Kim, Jiabin Dong, Lili Wang, Jimin Xu, Dan Zhang, Ruping Yan, Hao Zou, Haiying Chen, Xi Liu, Yun Zhu, Yu Xue, Jia Zhou, Qiang Shen. Chemoprevention of breast cancer by targeting glucose metabolism with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5066.

Role of Glucagon-Like Peptide-1 in Appetite Regulation in Patients with Morbid Obesity and Leptin Resistance

To contribute to the outstanding discussion of suggested reasons of obesity, including the hormonal disorders, and how to deal and avoid them, this research attempts to investigate and control the energy balance disturbances resulting from hormonal disorders that may cause obesity by dysregulating appetite. A total of 88 participants are recruited, among whom 50 and 38 were allocated to the control and patients groups, respectively. Venous blood samples are collected from the participants at different time points for the quantification of the pre-prandial and 2, 6 and 12 h postprandial levels of lipid markers, including total cholesterol, high density lipoproteins, low density lipoproteins, very low density lipoproteins, and triacylglycerol, and the appetite-related hormones leptin and intestinal hormones glucagon-like peptide (GLP-1). In healthy controls, leptin levels increased prior to eating, decreased after eating, and then increased to induce hunger at several hours after eating. By contrast, the pre-prandial and postprandial leptin levels of the patients group did not show statistically significant differences. Healthy controls had moderate GLP-1 levels, whereas patients with obesity and leptin resistance had high GLP-1 levels. The GLP-1 was found to be secreted in response to high postprandial energy levels as an adaptation to leptin resistance. This study elucidates the relationship between the adipose tissue hormone leptin and GLP-1 in patients with morbid obesity. Findings of using GLP-1 as an appetite regulator for the morbidly obese patients and have leptin resistance (resistance to its action in appetite regulation), presented here, should provide a valuable information for further experimental investigations.

Abstract 4883: Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152

Abstract Most mammalian cells use glucose as the primary fuel source. Glucose is metabolized via glycolysis to pyruvate, which is further transferred into mitochondria for generation of ATP through the Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small-molecule glucose metabolism modulator, was developed using structure-/fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed inhibited cell growth. Intriguingly, HJC0152 decreased activity and protein level of LDHA, which resulted in a decrease of lactate production in breast cancer cells. In addition, these cells also exhibited a decrease of glucose uptake by reducing Glut1 and HK2 protein level and modulation of the expression of glycolytic enzymes. Furthermore, HJC0152 treatment causes decreased mitochondrial membrane energy potential, resulting in significantly reduced level of intracellular ATP in MDA-MB-231 cells. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutics for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases. Citation Format: Hyejin Kim, Jiabin Dong, Jimin Xu, Dengfeng Li, Zhi Zheng, Na Ye, Ziwei Zhang, Haiying Chen, Jia Zhou, Qiang Shen. Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4883.

Abstract P1-02-08: Reprogramming glucose metabolism and energy production in breast cancer cells

Abstract Most mammalian cells use glucose as a main fuel source. Glucose is metabolized via glycolysis to pyruvate, which enters the mitochondria and then generates ATP through Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward aerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small molecule glucose metabolism modulator, was developed using structure- and fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed decreased activity and protein level of LDHA, which resulted in a decrease lactate production. In addition, these cells also exhibited decreased glucose uptake and HK2 protein level. Furthermore, the amount of intracellular ATP in MDA-MB-231 cells was significantly reduced. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutic for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases.This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), Holden Family Research Grant in BC Prevention (QS), and NCI PREVENT Program HHSN26100002 (QS). Citation Format: Kim H, Dong J, Xu J, Li D, Zheng Z, Ye N, Zhang Z, Chen H, Zhou J, Shen Q. Reprogramming glucose metabolism and energy production in breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-08.

FIAT Deletion Increases Bone Mass But Does Not Prevent High-Fat-Diet-Induced Metabolic Complications.

Factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT) interacts with ATF4 to repress its transcriptional activity. We performed a phenotypic analysis of Fiat-deficient male mice (Fiat−/Y) at 8 and 16 weeks of age. Microcomputed tomography analysis of the distal femur demonstrated 46% and 13% age-dependent increases in trabecular bone volume and thickness, respectively, in Fiat−/Y mice. Cortical bone measurements at the femoral midshaft revealed a substantial increase in cortical thickness in older Fiat−/Y mice. Bone gain was related to increased mineral apposition rate and increased osteoblast function. Femoral stiffness and strength were substantially increased in Fiat−/Y compared with wild-type (WT) mice. We also investigated whether FIAT contributes to metabolic function. When fed standard mouse chow, Fiat−/Y animals were glucose-tolerant. However, when fed a high-fat diet (HFD) for 8 weeks, Fiat−/Y mice gained more weight than control mice, with a specific increase in white adipose tissue fat mass. The increase in fat mass was due to reduced energy expenditure, which correlated with reduced fatty acid oxidation and lipolysis in the adipose tissue of mutant mice. The expression of the Scd1 gene, involved in lipogenesis, was upregulated in the subcutaneous adipose tissue of Fiat−/Y mice. Moreover, HFD-fed Fiat−/Y mice exhibited increased circulating leptin and insulin levels relative to WT mice, demonstrating that endocrine abnormalities are associated with the disturbance in energy balance. We conclude that Fiat−/Y mice exhibited an anabolic bone phenotype but displayed increased susceptibility to developing metabolic-related disorders when consuming an HFD.

Thermal stress effects on energy resource allocation and oxygen consumption rate in the juvenile sea cucumber, Holothuria scabra (Jaeger, 1833)

Water temperature is a key factor in aquaculture production of the commercially valuable sea cucumber Holothuria scabra. Knowledge is scarce about actual energetic costs that can be associated with internal acclimatization processes as a response to thermal extremes. In the present study changes in cellular energy allocation, oxygen consumption rate and energy related enzymes' activity (IDH and LDH) were measured in juvenile H. scabra, held at different temperatures: 21, 27 and 33°C. The results showed that the steady temperature change (1°C/day) to both temperature treatments, until reaching the testing temperatures (day 0), clearly affected cellular energy consumption and available energy reserves, measured in the respiratory tree and muscle tissue, respectively. However, 15 and 30days after acclimation, the initial differences in cellular energy allocation between treatments decreased. In contrast to the variations measured in cellular energy allocation, oxygen consumption was highest at 33°C and lowest at 21°C at all three measurement times. Moreover, a significant positive correlation between oxygen consumption rate and temperature was detected at day 15 and day 30. Likewise, a shift from anaerobic to aerobic energy metabolism, indicated by changes in LDH and IDH activities, was observed in the animals from the warm temperature treatment. Results imply that juvenile H. scabra were able to recover from initial disturbances in energy balance, caused by the incremental temperature change of ±6°C. Over the experimental period of 30days, elevated temperature did however, lead to a metabolic shift and more efficient energy turnover, indicated by changes in oxygen consumption rate, LDH and IDH. The synergy of cellular energy allocation and oxygen consumption proved to be a viable indicator to assess the capability of sea cucumbers like H. scabra to cope with extreme temperature conditions. Surprisingly, juvenile H. scabra were able to sustain their energy balance and oxygen consumption rate within the homeostatic range, even at 33°C. Thus, we assume that rearing temperatures of 33°C might be possible, which could improve aquaculture production of H. scabra. However, further research is required to understand the mechanisms and effects of acclimation under aquaculture conditions. Statement of relevanceThe sea cucumber H. scabra is considered a promising aquaculture candidate in the tropics. The commercial interest in H. scabra has led to a great number of attempts to culture this species e.g. in Madagascar, Tanzania, India and Indonesia, where the farming of this species also showed a great potential to increase the livelihood of the local community. Although, considerable research effort has been put into the advancement of the production cycle, fundamental knowledge, e.g. on physiological adjustments due to sub-optimal rearing conditions, remains scarce for H. scabra. Water temperature has been identified as crucial factor, determining production efficiency. In our manuscript we introduce an innovative approach, for the assessment of shifts in the energy budget as well as in metabolic pathways, to detect thermal stress in juvenile H. scabra. Our results show that the combined application of cellular energy allocation (CEA) and measurement of the oxygen consumption rate (OCR) as well as the activity of two metabolic key enzymes: iso-citrate dehydrogenase (IDH) and lactate dehydrogenase (LDH), is a strong analytical tool to evaluate whole animal homeostasis under thermal extremes. To our knowledge this is the first study in which the method of CEA was optimized for the application on isolated muscle and respiratory tree tissue of a sea cucumber, like H. scabra. Hence, our results provide original insights into the thermal acclimation physiology of H. scabra, which provides crucial knowledge for setting up optimal culture conditions for this highly valuable aquaculture candidate.Moreover, our results show that juvenile H. scabra were strongly affected by rapid temperature changes, exhibiting distinct differences in metabolic adjustments as response to short-term cold and warm acclimation, but were able to restore homeostatic conditions at constant cold and warm temperature extremes. Concerning aquaculture practices, these findings imply that CEA might be a good condition indicator to evaluate the overall metabolic status in sea cucumbers. Moreover, rapid temperature fluctuations seem to provoke much higher energetic costs in juvenile H. scabra than constant extreme temperature conditions, which is important to consider in daily management practices.The OCR revealed an enhanced metabolism at warmer temperature conditions, throughout the entire experimental period. Likewise, the warm exposed animals were shifting their energy turnover from a more anaerobic to a more aerobic state, indicated by changes in LDH and IDH activities, and showed increased foraging activity at all times. The combined outcome of CEA, OCR and activities of energy metabolism related enzymes indicates, that the increased metabolic activity in juvenile H. scabra, as response to warmer temperature, was well within the homeostatic range. Thus, contrary to our expectations, a rearing temperature of up to 33°C might presumably be favourable for the aquaculture of H. scabra.

Insulin exposure during in vitro bovine oocyte maturation changes blastocyst gene expression and developmental potential.

Metabolic imbalance impairs fertility, because changes in concentrations of metabolites and hormones in the blood and follicular fluid create an unfavourable environment for early embryonic development. Insulin is a key metabolic hormone known for its effects on fertility: insulin concentrations are increased during energy balance disturbances in diabetes or metabolic syndrome. Still, insulin is frequently used at supraphysiological concentrations for embryo in vitro culture with unknown consequences for the developmental potential of the offspring. In the present study we investigated the effects of insulin exposure during in vitro bovine oocyte maturation on developmental rates, embryo quality and gene expression. Supplementation of the maturation media with insulin at 10 or 0.1 µg mL-1 decreased blastocyst rates compared with an insulin-free control (19.8 ± 1.3% and 20.4 ± 1.3% vs 23.8 ± 1.3%, respectively; P < 0.05) and led to increased cell numbers (nearly 10% more cells on Day 8 compared with control; P < 0.05). Transcriptome analysis revealed significant upregulation of genes involved in lipid metabolism, nuclear factor (erythroid-derived 2)-like 2 (NRF2) stress response and cell differentiation, validated by quantitative polymerase chain reaction. To conclude, the results of the present study demonstrate that insulin exposure during in vitro oocyte maturation has a lasting effect on the embryo until the blastocyst stage, with a potential negative effect in the form of specific gene expression perturbations.

Changes in some hematobiochemical and hormonal profile in Barki sheep with various reproductive statuses

The current work aimed to test the fit hypothesis; does the animal reproductive status have an impact on the hormonal milieu of the animals and consequently its body metabolic status? In this study, we assessed the changes in circulating hormones, key metabolites and blood parameters taking place during different stages of the estrous cycle and pregnancy in Egyptian Barki ewes. An ultrasonographic examination as well as blood sampling were conducted, before the morning feeding, on clinically healthy cyclic non-pregnant (n=7) and pregnant (n=9) Barki ewes at early- (d 60±5 post breeding [PB]), mid- (d 90±5 PB) and late- (d 135±5 PB) stage of pregnancy. The results showed marked changes in certain biochemical parameters of sheep blood serum during pregnancy as compared to luteal and/or follicular stages. Pregnancy was associated with significant higher levels of progesterone, glutathione peroxidase, malondialdehyde, nitric oxide and HDL. Samples from cyclic animals showed higher levels of insulin, T3, T4, superoxide dismutase and glucose. Nevertheless, leptin, triglycerides, cholesterol, VLDL, LDL and blood parameters did not vary between pregnant and non-pregnant animals. From these results we can conclude that the reproductive state influence on reproductive (progesterone) and metabolic (T3, T4 and insulin) hormonal levels, lipid peroxidation and body metabolism, which could have long-lasting consequences and therefore should be taken into consideration during the early prediction and/or diagnosis of metabolic diseases related to disturbance in energy balance and/or oxidative stress in Barki ewes.

Prebiotic Fiber Consumption Decreases Energy Intake in Overweight and Obese Children

Excess energy intake is thought to be a major driver of the obesity epidemic and even small disturbances in energy balance may lead to the onset of pediatric obesity. Prebiotic fiber improves appetite regulation and decreases energy intake in obese adults; however, its' therapeutic potential in the obese pediatric population has not been investigated. To determine the effect of prebiotic fiber intake on prospective food consumption and energy intake in the obese pediatric population, 39 male and female overweight and obese children (7‐12y) consumed 1) 8 g/d of prebiotic fiber (1:1 oligofructose:inulin); or 2) equicaloric dose of maltodextrin for 16 wk. Subjective appetite ratings were obtained before and after an ad libitum breakfast buffet at 0 and 16 wk as well as Children's Eating Behaviour Questionnaire (CEBQ) scores. Energy intake was measured at the breakfast buffet and in weighed 3‐day food records. The first of 2 cohorts to complete the study showed a decreased desire to eat following fiber supplementation (p=0.02). There was also a trend for increased fullness and decreased prospective food consumption in the fiber group. CEBQ scores showed increased satiety responsiveness with fiber consumption (p=0.01). The change in energy intake at the final breakfast buffet was 84 kcal lower with fiber versus placebo. In conclusion, long term prebiotic fiber intake may lead to reductions in energy intake that positively impact body weight. Potential causes for decreased energy intake include heightened satiety responsiveness and fullness following fiber consumption. Funded by CIHR, BMO Financial Group,Alberta Children's Hospital Research Institute.

The Suprachiasmatic Nucleus Controls Circadian Energy Metabolism and Hepatic Insulin Sensitivity

Disturbances in the circadian system are associated with the development of type 2 diabetes mellitus. Here, we studied the direct contribution of the suprachiasmatic nucleus (SCN), the central pacemaker in the circadian system, in the development of insulin resistance. Exclusive bilateral SCN lesions in male C57Bl/6J mice, as verified by immunochemistry, showed a small but significant increase in body weight (+17%), which was accounted for by an increase in fat mass. In contrast, mice with collateral damage to the ventromedial hypothalamus and paraventricular nucleus showed severe obesity and insulin resistance. Mice with exclusive SCN ablation revealed a loss of circadian rhythm in activity, oxygen consumption, and food intake. Hyperinsulinemic–euglycemic clamp analysis 8 weeks after lesioning showed that the glucose infusion rate was significantly lower in SCN lesioned mice compared with sham-operated mice (−63%). Although insulin potently inhibited endogenous glucose production (−84%), this was greatly reduced in SCN lesioned mice (−7%), indicating severe hepatic insulin resistance. Our data show that SCN malfunctioning plays an important role in the disturbance of energy balance and suggest that an absence of central clock activity, in a genetically intact animal, may lead to the development of insulin resistance.

Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice

The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of the receptor in obesity and metabolic complications is still elusive. In the present study, we investigated the impact of GPRC6A deficiency in a murine model of diet-induced obesity (DIO). Male Gprc6a knockout (KO) mice and WT littermates were subjected to a high-fat diet (HFD) for 25 weeks and exposed to comprehensive metabolic phenotyping. A significant increase in body weight, corresponding to a selective increase in body fat, was observed in Gprc6a KO mice exposed to an HFD relative to WT controls. The obese phenotype was linked to subtle perturbations in energy homoeostasis as GPRC6A deficiency resulted in chronic hyperphagia and decreased locomotor activity. Moreover, diet-induced obese Gprc6a KO mice had increased circulating insulin and leptin levels relative to WT animals, thereby demonstrating that endocrine abnormalities associate with the reported disturbances in energy balance. The phenotype was further accompanied by disruptions in glucose metabolism showing that Gprc6a KO mice on an HFD display increased susceptibility to develop metabolic-related disorders. Altogether, these data suggest that the amino acid sensing receptor GPRC6A plays an important role in resistance to DIO and metabolic complications. Future studies will illuminate the underlying molecular mechanisms mediating the herein reported findings and potentially facilitate the development of novel therapeutic compounds targeting the GPRC6A receptor.

Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice

The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of the receptor in obesity and metabolic complications is still elusive. In the present study, we investigated the impact of GPRC6A deficiency in a murine model of diet-induced obesity (DIO). Male Gprc6a knockout (KO) mice and WT littermates were subjected to a high-fat diet (HFD) for 25 weeks and exposed to comprehensive metabolic phenotyping. A significant increase in body weight, corresponding to a selective increase in body fat, was observed in Gprc6a KO mice exposed to an HFD relative to WT controls. The obese phenotype was linked to subtle perturbations in energy homoeostasis as GPRC6A deficiency resulted in chronic hyperphagia and decreased locomotor activity. Moreover, diet-induced obese Gprc6a KO mice had increased circulating insulin and leptin levels relative to WT animals, thereby demonstrating that endocrine abnormalities associate with the reported disturbances in energy balance. The phenotype was further accompanied by disruptions in glucose metabolism showing that Gprc6a KO mice on an HFD display increased susceptibility to develop metabolic-related disorders. Altogether, these data suggest that the amino acid sensing receptor GPRC6A plays an important role in resistance to DIO and metabolic complications. Future studies will illuminate the underlying molecular mechanisms mediating the herein reported findings and potentially facilitate the development of novel therapeutic compounds targeting the GPRC6A receptor.

Energy homeostasis as an integrative tool for assessing limits of environmental stress tolerance in aquatic invertebrates

Energy balance is a fundamental requirement of stress adaptation and tolerance. We explore the links between metabolism, energy balance and stress tolerance using aquatic invertebrates as an example and demonstrate that using key parameters of energy balance (aerobic scope for growth, reproduction and activity; tissue energy status; metabolic rate depression; and compensatory onset of anaerobiosis) can assist in integrating the effects of multiple stressors and their interactions and in predicting the whole-organism and population-level consequences of environmental stress. We argue that limitations of both the amount of available energy and the rates of its acquisition and metabolic conversions result in trade-offs between basal maintenance of a stressed organism and energy costs of fitness-related functions such as reproduction, development and growth and can set limit to the tolerance of a broad range of environmental stressors. The degree of stress-induced disturbance of energy balance delineates transition from moderate stress compatible with population persistence (pejus range) to extreme stress where only time-limited existence is possible (pessimum range). It also determines the predominant adaptive strategy of metabolic responses (energy compensation vs. conservation) that allows an organism to survive the disturbance. We propose that energy-related biomarkers can be used to determine the conditions when these metabolic transitions occur and thus predict ecological consequences of stress exposures. Bioenergetic considerations can also provide common denominator for integrating stress responses and predicting tolerance limits under the environmentally realistic scenarios when multiple and often variable stressors act simultaneously on an organism. Determination of bioenergetic sustainability at the organism's level (or lack thereof) has practical implications. It can help identify the habitats and/or conditions where a population can survive (even if at the cost of reduced reproduction and growth) and those that are incapable of supporting viable populations. Such an approach will assist in explaining and predicting the species' distribution limits in the face of the environmental change and informing the conservation efforts and resource management practices.

Distinct associations between energy balance and the sleep characteristics slow wave sleep and rapid eye movement sleep

Epidemiologically, an inverse relationship between body mass index (BMI) and sleep duration is observed. Intra-individual variance in the amount of slow wave sleep (SWS) or rapid eye movement (REM) sleep has been related to variance of metabolic and endocrine parameters, which are risk factors for the disturbance of energy balance (EB). To investigate inter-individual relationships between EB (EB= energy intake-energy expenditure∣, MJ/24 h), SWS or REM sleep, and relevant parameters in normal-weight men during two 48 h stays in the controlled environment of a respiration chamber. A total of 16 men (age 23±3.7 years, BMI 23.9±1.9 kg m(-2)) stayed in the respiration chamber twice for 48 h to assure EB. Electroencephalography was used to monitor sleep (2330-0730 hrs). Hunger and fullness were scored by visual analog scales; mood was determined by State Trait Anxiety Index-state and food reward by liking and wanting. Baseline blood and salivary samples were collected before breakfast. Subjects were fed in EB, except for the last dinner, when energy intake was ad libitum. The subjects slept on average 441.8±49 min per night, and showed high within-subject reliability for the amount of SWS and REM sleep. Linear regression analyses showed that EB was inversely related to the amount of SWS (r=-0.43, P<0.03), and positively related to the amount of REM sleep (r=0.40, P<0.05). Relevant parameters such as hunger, reward, stress and orexigenic hormone concentrations were related to overeating, as well as to the amount of SWS and REM sleep, however, after inclusion of these parameters in a multiple regression, the amount of SWS and REM sleep did not add to the explained variance of EB, which suggests that due to their individual associations, these EB parameters are mediator variables. A positive EB due to overeating, was explained by a smaller amount of SWS and higher amount of REM sleep, mediated by hunger, fullness, State Trait Anxiety Index-state scores, glucose/insulin ratio, and ghrelin and cortisol concentrations.

The effects of calcium and glucose supplementation on bone of young female rats in case of disturbances in energy balance caused by their food restriction and exercise

Background Female athletes, with a strong awareness of their weight loss, are prone to restrict their food intake. A major concern arisen from such athletes’ daily training would be an imbalance of energy intake and energy expenditure which resulted in an osteoporotic fracture. Calcium (Ca) is a major mineral content in bone, otherwise Glucose (Glu) is an energy source. It is not clear whether Ca or Glu supplementation have a positive effect on bone in case of disturbances in energy balance caused by their food restriction and exercise. Methods