Conditional Deletion of ß-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity.

ß-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, ß-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether ß-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female ß-catenin flox mice, to specifically delete ß-catenin expression in the mediobasal hypothalamus (MBH-ß-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-ß-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-ß-cat KO mice were significantly heavier than the control mice in both sexes (p < 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-ß-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for ß-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.

Bioenergetic costs and the evolution of noise regulation by microRNAs.

Noise control, together with other regulatory functions facilitated by microRNAs (miRNAs), is believed to have played important roles in the evolution of multicellular eukaryotic organisms. miRNAs can dampen protein fluctuations via enhanced degradation of messenger RNA (mRNA), but this requires compensation by increased mRNA transcription to maintain the same expression levels. The overall mechanism is metabolically expensive, leading to questions about how it might have evolved in the first place. We develop a stochastic model of miRNA noise regulation, coupled with a detailed analysis of the associated metabolic costs. Additionally, we calculate binding free energies for a range of miRNA seeds, the short sequences which govern target recognition. We argue that natural selection may have fine-tuned the Michaelis-Menten constant [Formula: see text] describing miRNA-mRNA affinity and show supporting evidence from analysis of experimental data. [Formula: see text] is constrained by seed length, and optimal noise control (minimum protein variance at a given energy cost) is achievable for seeds of 6 to 7 nucleotides in length, the most commonly observed types. Moreover, at optimality, the degree of noise reduction approaches the theoretical bound set by the Wiener-Kolmogorov linear filter. The results illustrate how selective pressure toward energy efficiency has potentially shaped a crucial regulatory pathway in eukaryotes.

Reciprocal Regulation of Hepatic TGF-ß1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.

Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-ß1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-ß1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-ß1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-ß1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-ß1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-ß1→Foxo1→TGF-ß1 looping by deleting TGF-ß1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-ß1→Foxo1→TGF-ß1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. ARTICLE HIGHLIGHTS: Hepatic TGF-ß1 levels are increased in obese humans and mice. Hepatic TGF-ß1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-ß1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-ß1→Foxo1→TGF-ß1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse.

Adipose tissue inflammation and insulin resistance are hallmarks in the development of metabolic diseases resulting from overweight and obesity, such as type 2 diabetes and non-alcoholic fatty liver disease. In obesity, adipocytes predominantly secrete proinflammatory adipokines that further promote adipose tissue dysfunction with negative effects on local and systemic insulin sensitivity. Expression of the serpin vaspin (SERPINA12) is also increased in obesity and type 2 diabetes, but exhibits compensatory roles in inflammation and insulin resistance. This has in part been demonstrated using vaspin-transgenic mice. We here report a new mouse line (h-vaspinTG) with transgenic expression of human vaspin in adipose tissue that reaches vaspin concentrations three orders of magnitude higher than wild type controls (>200 ng/ml). Phenotyping under chow and high-fat diet conditions included glucose-tolerance tests, measurements of energy expenditure and circulating parameters, adipose tissue and liver histology. Also, ex vivo glucose uptake in isolated adipocytes and skeletal muscle was analyzed in h-vaspinTG and littermate controls. The results confirmed previous findings, revealing a strong reduction in diet-induced weight gain, fat mass, hyperinsulinemia, -glycemia and -cholesterolemia as well as fatty liver. Insulin sensitivity in adipose tissue and muscle was not altered. The h-vaspinTG mice showed increased energy expenditure under high fat diet conditions, that may explain reduced weight gain and overall metabolic improvements. In conclusion, this novel human vaspin-transgenic mouse line will be a valuable research tool to delineate whole-body, tissue- and cell-specific effects of vaspin in health and disease.

Astrocytic circadian clock control of energy expenditure by transcriptional stress responses in the ventromedial hypothalamus.

Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core-clock gene Bmal1 within Gfap-expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo-caloric diet, under high-fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER-stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.

The ABA/LANCL1/2 Hormone/Receptor System Controls Adipocyte Browning and Energy Expenditure.

The abscisic acid (ABA)/LANC-like protein 1/2 (LANCL1/2) hormone/receptor system regulates glucose uptake and oxidation, mitochondrial respiration, and proton gradient dissipation in myocytes. Oral ABA increases glucose uptake and the transcription of adipocyte browning-related genes in rodent brown adipose tissue (BAT). The aim of this study was to investigate the role of the ABA/LANCL system in human white and brown adipocyte thermogenesis. Immortalized human white and brown preadipocytes, virally infected to overexpress or silence LANCL1/2, were differentiated in vitro with or without ABA, and transcriptional and metabolic targets critical for thermogenesis were explored. The overexpression of LANCL1/2 increases, and their combined silencing conversely reduces mitochondrial number, basal, and maximal respiration rates; proton gradient dissipation; and the transcription of uncoupling genes and of receptors for thyroid and adrenergic hormones, both in brown and in white adipocytes. The transcriptional enhancement of receptors for browning hormones also occurs in BAT from ABA-treated mice, lacking LANCL2 but overexpressing LANCL1. The signaling pathway downstream of the ABA/LANCL system includes AMPK, PGC-1α, Sirt1, and the transcription factor ERRα. The ABA/LANCL system controls human brown and "beige" adipocyte thermogenesis, acting upstream of a key signaling pathway regulating energy metabolism, mitochondrial function, and thermogenesis.

KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure.

Obesity is a growing global epidemic that can cause serious adverse health consequences, including insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Obesity development can be attributed to energy imbalance and metabolic inflexibility. Here, we demonstrated that lack of Kelch-like protein 3 (KLHL3) mitigated the development of obesity, IR, and NAFLD by increasing energy expenditure. KLHL3 mutations in humans cause Gordon's hypertension syndrome; however, the role of KLHL3 in obesity was previously unknown. We examined differences in obesity-related parameters between control and Klhl3-/- mice. A significant decrease in body weight concomitant with fat mass loss and improved IR and NAFLD were observed in Klhl3-/- mice fed a high-fat (HF) diet and aged. KLHL3 deficiency inhibited obesity, IR, and NAFLD by increasing energy expenditure with augmentation of O2 consumption and CO2 production. Delivering dominant-negative (DN) Klhl3 using adeno-associated virus into mice, thereby dominantly expressing DN-KLHL3 in the liver, ameliorated diet-induced obesity, IR, and NAFLD. Finally, adenoviral overexpression of DN-KLHL3, but not wild-type KLHL3, in hepatocytes revealed an energetic phenotype with an increase in the oxygen consumption rate. The present findings demonstrate a novel function of KLHL3 mutation in extrarenal tissues, such as the liver, and may provide a therapeutic target against obesity and obesity-related diseases.

Effects of maternal high-fat diet on the hypothalamic components related to food intake and energy expenditure in mice offspring.

Maternal exposure to a high-fat diet (HFD) during pregnancy and lactation has been related to changes in the hypothalamic circuits involved in the regulation of food intake. Furthermore, maternal HFD during the critical period of development can alter the offspring's metabolic programming with long-term repercussions. This study systematically reviewed the effects of HFD consumption during pre-pregnancy, pregnancy and/or lactation. The main outcomes evaluated were food intake, body weight and cellular or molecular aspects of peptides and hypothalamic receptors involved in the regulation of energy balance in mice. Two independent authors performed a search in the electronic databases Medline/PubMed, LILACS, Web of Science, EMBASE, SCOPUS and Sigle via Open Gray. The experimental studies of mice exposed to HFD during pregnancy and/or lactation that evaluated body composition, food intake, energy expenditure and hypothalamic components related to energy balance were included. Internal validity was assessed using the SYRCLE risk of bias. The Kappa index was measured to analyze the agreement between reviewers. The PRISMA statement was used to report this systematic review. Most studies demonstrated that there was a higher body weight, body fat deposits and food intake, as well as alterations in the expression of hypothalamic neuropeptides in offspring that consumed HFD. Therefore, the maternal diet can affect the phenotype and metabolism of the offspring, in addition to harming the hypothalamic circuits and favoring the orexigenic pathways.

Resting Energy Expenditure and Body Composition in Children and Adolescents With Genetic, Hypothalamic, Medication-Induced or Multifactorial Severe Obesity.

Background: Pediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure. Aim: To investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with or without underlying medical causes. Methods: This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic centre that evaluated endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio between measured REE (mREE) and predicted REE (Schofield equations), REE%, was calculated, with decreased mREE defined as REE% ≤90% and elevated mREE ≥110%. Additionally, the influence of fat-free-mass (FFM) on mREE was evaluated using multiple linear regression. Results: We included 292 patients (146 [50%] with body composition measurements), of which 218 (75%) patients had multifactorial obesity and 74 (25%) an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p<0.01). In 9 children with pseudohypoparathyroidism type 1a, mean REE% was similar (100.4 ± 5.1). Across all patients, mREE was decreased in 60 (21%) patients and elevated in 69 (24%) patients. After adjustment for FFM, mREE did not differ between patients within each of the subgroups of underlying medical causes compared to multifactorial obesity (all p>0.05). Conclusions: In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Consistent with previous studies, almost half of patients had decreased or elevated mREE. This knowledge is important for patient-tailored treatment, e.g. personalized dietary and physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE.

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.

The KRAB Domain-Containing Protein ZFP961 Represses Adipose Thermogenesis and Energy Expenditure through Interaction with PPARα.

Adipose thermogenesis plays a pivotal role in whole-body metabolic homeostasis. Although transcriptional mechanisms that promote thermogenesis are extensively studied, the negative regulatory network is still poorly understood. Here, a Krüppel-associated box (KRAB) domain-containing zinc finger protein, ZFP961, as a potent repressor of the thermogenic program is identified. ZFP961 expression is induced by cold and ß3-adrenergic agonist in adipose tissue. ZFP961 represses brown fat-selective gene expression and mitochondrial respiration without any effect on general adipogenesis in cultured adipocytes. Adipose-specific knockdown and overexpression of ZFP961 produce remarkable and opposite phenotypes of white fat remodeling. ZFP961 knockout mice display robust inguinal white adipose tissue browning, which is abolished by reexpression of full-length ZFP961, but not by KRAB domain-deleted ZFP961 mutant. ZFP961-deficient mice are cold tolerant and resistant to high-fat diet-induced obesity, hyperglycemia, and hepatic steatosis. ZFP961 suppresses thermogenic gene expression by directly interacting with PPARα and blocking its transcriptional activity, which can be completely negated by the PPARα agonist. The findings uncover ZFP961 as a critical physiological brake that limits adipose thermogenesis and provides insights into the regulatory mechanisms that maintain energy balance and tissue homeostasis.

Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9.

Cyclic nucleotides cAMP and cGMP are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis, but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo. Mice with targeted disruption of the PDE9 gene, Pde9a, were fed nutrient-matched high-fat (HFD) or low-fat diets. Pde9a -/- mice were resistant to HFD-induced obesity, exhibiting a global increase in energy expenditure, while brown adipose tissue (AT) had increased respiratory capacity and elevated expression of Ucp1 and other thermogenic genes. Reduced adiposity of HFD-fed Pde9a -/- mice was associated with improvements in glucose handling and hepatic steatosis. Cold exposure or treatment with ß-adrenergic receptor agonists markedly decreased Pde9a expression in brown AT and cultured brown adipocytes, while Pde9a -/- mice exhibited a greater increase in AT browning, together suggesting that the PDE9-cGMP pathway augments classical cold-induced ß-adrenergic/cAMP AT browning and energy expenditure. These findings suggest PDE9 is a previously unrecognized regulator of energy metabolism and that its inhibition may be a valuable avenue to explore for combating metabolic disease.

TLR4 deletion increases basal energy expenditure and attenuates heart apoptosis and ER stress but mitigates the training-induced cardiac function and performance improvement.

Strategies capable of attenuating TLR4 can attenuate metabolic processes such as inflammation, endoplasmic reticulum (ER) stress, and apoptosis in the body. Physical exercise has been a cornerstone in suppressing inflammation and dysmetabolic outcomes caused by TRL4 activation. Thus, the present study aimed to evaluate the effects of a chronic physical exercise protocol on the TLR4 expression and its repercussion in the inflammation, ER stress, and apoptosis pathways in mice hearts. Echocardiogram, RT-qPCR, immunoblotting, and histological techniques were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (TLR4 KO) mice submitted to a 4-week physical exercise protocol. Moreover, we performed a bioinformatics analysis to expand the relationship of Tlr4 mRNA in the heart with inflammation, ER stress, and apoptosis-related genes of several isogenic strains of BXD mice. The TLR4 KO mice had higher energy expenditure and heart rate in the control state but lower activation of apoptosis and ER stress pathways. The bioinformatics analysis reinforced these data. In the exercised state, the WT mice improved performance and cardiac function. However, these responses were blunted in the KO group. In conclusion, TLR4 has an essential role in the inhibition of apoptosis and ER stress pathways, as well as in the training-induced beneficial adaptations.

Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure.

Selenoprotein V (SELENOV) is a new and the least conserved member of the selenoprotein family. Herein we generated Selenov knockout (KO) mice to determine its in vivo function. The KO led to 16-19% increases (P < 0.05) in body weight that were largely due to 54% higher (P < 0.05) fat mass accumulation, compared with the wild-type (WT) controls. The extra fat accumulation in the KO mice was mediated by up-regulations of genes and proteins involved in lipogenesis (Acc, Fas, Dgat, and Lpl; up by 40%-1.1-fold) and down-regulations of lipolysis (Atgl, Hsl, Ces1d, and Cpt1a; down by 36-89%) in the adipose tissues. The KO also decreased (P < 0.05) VO2 consumption (14-21%), VCO2 production (14-16%), and energy expenditure (14-23%), compared with the WT controls. SELENOV and O-GlcNAc transferase (OGT) exhibited a novel protein-protein interaction that explained the KO-induced decreases (P < 0.05) of OGT protein (15-29%), activity (33%), and function (O-GlcNAcylation, 10-21%) in the adipose tissues. A potential cascade of SELENOV-OGT-AMP-activated protein kinase might serve as a central mechanism to link the biochemical and molecular responses to the KO. Overall, our data revealed a novel in vivo function and mechanism of SELENOV as a new inhibitor of body fat accumulation, activator of energy expenditure, regulator of O-GlcNAcylation, and therapeutic target of such related disorders.

Overexpression of translationally controlled tumor protein ameliorates metabolic imbalance and increases energy expenditure in mice.

BACKGROUND/OBJECTIVES: Translationally controlled tumor protein (TCTP) exhibits numerous biological functions. It has been shown to be involved in the regulation of glucose. However, its specific role in metabolism has not yet been clearly elucidated. Here, we aimed to assess the effect of TCTP overexpression on metabolic tissues and systemic energy metabolism. SUBJECTS/METHODS: We investigated whether TCTP can ameliorate the metabolic imbalance that causes obesity using TCTP-overexpressing transgenic (TCTP TG) mice. The mice were subjected to biochemical, morphological, physiological and protein expression studies to define the role of TCTP in metabolic regulation in response to normal chow diet (NCD) compared to high-fat diet (HFD) conditions, and cold environment. RESULTS: We found that TCTP TG mice show improved metabolic homeostasis under both of NCD and HFD conditions with simultaneous enhancements in glucose tolerance and insulin sensitivity. In particular, we found coincident increases in energy expenditure with significant upregulation of uncoupling protein 1 (UCP1) in the brown adipose tissue (BAT). Moreover, TCTP overexpressing mice exhibit significantly enhanced adaptive thermogenesis of BAT in response to cold exposure. CONCLUSIONS: Overexpression of TCTP ameliorated systemic metabolic homeostasis by stimulating UCP1-mediated thermogenesis in the BAT. This suggests that TCTP may function as a modulator of energy expenditure. This study suggests TCTP may serve as a therapeutic target for obesity and obesity-associated metabolic disorders including type 2 diabetes.

Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis.

Alzheimer's disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by 1H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.

GIP receptor deletion in mice confers resistance to high-fat diet-induced obesity via alterations in energy expenditure and adipose tissue lipid metabolism.

Glucose-dependent insulinotropic polypeptide (GIP) is best known as an incretin hormone that is secreted from K-cells of the proximal intestine, but evidence also implicates a role for GIP in regulating lipid metabolism and adiposity. It is well-established that GIP receptor knockout (GIPR KO) mice are resistant to diet-induced obesity; however, the factors mediating this effect remain unresolved. Accordingly, we aimed to elucidate the mechanisms leading to adiposity resistance in GIPR KO mice with a focus on whole-body energy balance and lipid metabolism in adipose tissues. Studies were conducted in age-matched male GIPR KO and wild-type (WT) mice fed a high-fat diet for 10 weeks. GIPR KO mice gained less body weight and fat mass compared to WT littermates, and this was associated with increased energy expenditure but no differences in food intake or fecal energy loss. Upon an oral lipid challenge, fatty acid storage in inguinal adipose tissue was significantly increased in GIPR KO compared with WT mice. This was not related to differential expression of lipoprotein lipase in adipose tissue. Adipose tissue lipolysis was increased in GIPR KO compared with WT mice, particularly following ß-adrenergic stimulation, and could explain why GIPR KO mice gain less adipose tissue despite increased rates of fatty acid storage in inguinal adipose tissue. Taken together, these results suggest that the GIPR is required for normal maintenance of body weight and adipose tissue mass by regulating energy expenditure and lipolysis.NEW & NOTEWORTHY GIPR KO mice fed a high-fat diet have reduced adiposity despite transporting more ingested lipids into adipose tissue. This can be partly explained by accelerated adipose tissue lipolysis and increased energy expenditure in GIPR KO mice. These new insights rationalize targeting the GIPR as part of a weight management strategy in obesity.

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson's Disease.

Aside from the classical motor symptoms, Parkinson's disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson's. In this study, we hypothesized that Parkinson's-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson's, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson's disease pathology. This study implicates the involvement of orexin in early Parkinson's-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson's disease symptomology.

Total Energy Expenditure and Functional Status in Older Adults: A Doubly Labelled Water Study.

OBJECTIVES: Higher total energy expenditure in free living conditions, regardless of any activity, has been strongly associated with a lower risk of mortality in healthy older adults. Also, a good performance in physical and functional tests is a marker of good functional prognosis. However, it is not yet clear what is the association between total energy expenditure and the performance in physical and functional tests. The objective of this study was to verify the association between the total energy expenditure of older adults measured by doubly labelled water and the performance in functional tests. DESIGN: Cross-sectional study. SETTINGS AND PARTICIPANTS: Fifty-six older people were recruited from health services linked to the participating institutions. MEASUREMENTS: Socio-demographic, anthropometric and clinical characteristics were assessed through the application of a structured questionnaire. Body composition was evaluated by isotopic dilution of deuterium oxide and functional status was assessed by the gait speed test, 6-minute walk test and handgrip strength. Total energy expenditure (GET) was assessed using the doubly labelled water method and the physical activity profile was verified using an activity monitor based on accelerometery. RESULTS: The results showed that the highest total energy expenditure correlated with the best performance in the gait speed tests (r = 0.266; p = 0.047), 6-minute walk test (r = 0.424; p = 0.001) and maximum handgrip strength (r = 0.478; p = 0.000). Multivariate regression analysis in a model adjusted for sex and fat-free mass revealed an association between total energy expenditure and the 6-minute walk test (ß = 1.790; t = 2.080; p = 0.044) and the number of sedentary events ( ß = 6.389; t = 2.147; p = 0.038). CONCLUSION: The results of this study suggest that, in clinical practice, older individuals with lower gait speed, worse performance in the 6-minute walk test and lower handgrip strength, may have lower total energy expenditure, being the stimulus for its increase important for the prevention of possible problems related to low energy expenditure.