Volume 4 | No. 6 | June 2015MinireviewGhrelinT.D. Müller, R. Nogueiras, M.L. Andermann, Z.B. Andrews, S.D. Anker, J. Argente, R.L. Batterham, S.C. Benoit, C.Y. Bowers, F. Broglio, F.F. Casanueva, D. D'Alessio, I. Depoortere, A. Geliebter, E. Ghigo, P.A. Cole, M. Cowley, D.E. Cummings, A. Dagher, S. Diano, S.L. Dickson, C. Diéguez, R. Granata, H.J. Grill, K. Grove, K.M. Habegger, K. Heppner, M.L. Heiman, L. Holsen, B. Holst, A. Inui, J.O. Jansson, H. Kirchner, M. Korbonits, B. Laferrère, C.W. LeRoux, M. Lopez, S. Morin, M. Nakazato, R. Nass, D. Perez-Tilve, P.T. Pfluger, T.W. Schwartz, R.J. Seeley, M. Sleeman, Y. Sun, L. Sussel, J. Tong, M.O. Thorner, A.J. van der Lely, L.H.T. van der Ploeg, J.M. Zigman, M. Kojima, K. Kangawa, R.G. Smith, T. Horvath, M.H. Tschöp Abstract
The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.
Scope of review
In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery.
In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism. [Hide abstract]
Original Research ArticleIntegration of body temperature into the analysis of energy expenditure in the mouseGustavo Abreu-Vieira, Cuiying Xiao, Oksana Gavrilova, Marc L. Reitman Abstract
We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature.
The effect of environmental temperature (4–33 °C) on body temperature, energy expenditure, physical activity, and food intake in various mice (chow diet, high-fat diet, Brs3-/y
, lipodystrophic) was measured using continuous monitoring.
Body temperature depended most on circadian phase and physical activity, but also on environmental temperature. The amounts of energy expenditure due to basal metabolic rate (calculated via a novel method), thermic effect of food, physical activity, and cold-induced thermogenesis were determined as a function of environmental temperature. The measured resting defended body temperature matched that calculated from the energy expenditure using Fourier's law of heat conduction. Mice defended a higher body temperature during physical activity. The cost of the warmer body temperature during the active phase is 4–16% of total daily energy expenditure. Parameters measured in diet-induced obese and Brs3-/y
mice were similar to controls. The high post-mortem heat conductance demonstrates that most insulation in mice is via physiological mechanisms.
At 22 °C, cold-induced thermogenesis is ~120% of basal metabolic rate. The higher body temperature during physical activity is due to a higher set point, not simply increased heat generation during exercise. Most insulation in mice is via physiological mechanisms, with little from fur or fat. Our analysis suggests that the definition of the upper limit of the thermoneutral zone should be re-considered. Measuring body temperature informs interpretation of energy expenditure data and improves the predictiveness and utility of the mouse to model human energy homeostasis. [Hide abstract]
Original Research ArticleBrain-derived neurotrophic factor is required for axonal growth of selective groups of neurons in the arcuate nucleusGuey-Ying Liao, Karine Bouyer, Anna Kamitakahara, Niaz Sahibzada, Chien-Hua Wang, Michael Rutlin, Richard B. Simerly, Baoji Xu Abstract
Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development, and the Bdnf
gene produces two populations of transcripts with either a short or long 3' untranslated region (3' UTR). Deficiencies in BDNF signaling have been shown to cause severe obesity in humans; however, it remains unknown how BDNF signaling impacts the organization of neuronal circuits that control energy balance.
We examined the role of BDNF on survival, axonal projections, and synaptic inputs of neurons in the arcuate nucleus (ARH), a structure critical for the control of energy balance, using Bdnfklox/klox
mice, which lack long 3' UTR Bdnf mRNA and develop severe hyperphagic obesity.
We found that a small fraction of neurons that express the receptor for BDNF, TrkB, also expressed proopiomelanocortin (POMC) or neuropeptide Y (NPY)/agouti-related protein (AgRP) in the ARH. Bdnfklox/klox
mice had normal numbers of POMC, NPY, and TrkB neurons in the ARH; however, retrograde labeling revealed a drastic reduction in the number of ARH axons that project to the paraventricular hypothalamus (PVH) in these mice. In addition, fewer POMC and AgRP axons were found in the dorsomedial hypothalamic nucleus (DMH) and the lateral part of PVH, respectively, in Bdnfklox/klox
mice. Using immunohistochemistry, we examined the impact of BDNF deficiency on inputs to ARH neurons. We found that excitatory inputs onto POMC and NPY neurons were increased and decreased, respectively, in Bdnfklox/klox
mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice.
This study shows that the majority of TrkB neurons in the ARH are distinct from known neuronal populations and that BDNF plays a critical role in directing projections from these neurons to the DMH and PVH. We propose that hyperphagic obesity due to BDNF deficiency is in part attributable to impaired axonal growth of TrkB-expressing ARH neurons. [Hide abstract]
Original Research ArticleCholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolismJae Hoon Jeong, Dong Kun Lee, Clemence Blouet, Henry H. Ruiz, Christoph Buettner, Streamson Chua Jr., Gary J. Schwartz, Young-Hwan Jo Abstract
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Brown adipose tissue (BAT) thermogenesis is critical in maintaining body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous thermosensory signals and regulates adaptive thermogenesis. Here, we study the function and synaptic connectivity of input from DMH cholinergic neurons to sympathetic premotor neurons in the raphe pallidus (Rpa).
In order to selectively manipulate DMH cholinergic neuron activity, we generated transgenic mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the Cre-LoxP technique. In addition, we used an adeno-associated virus carrying the Cre recombinase gene to delete the floxed Chat
gene in the DMH. Physiological studies in response to optogenetic stimulation of DMH cholinergic neurons were combined with gene expression and immunocytochemical analyses.
A subset of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is associated with reduced body core temperature. Furthermore, elevated DMH cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 (Ucp1
) and peroxisome proliferator-activated receptor γ coactivator 1 α (Pgc1α
) mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor antagonists into the 4th ventricle abolishes the effect of optical stimulation. Single cell qRT-PCR analysis of retrogradely identified BAT-projecting neurons in the Rpa shows that all M2 receptor-expressing neurons contain tryptophan hydroxylase 2. In animals lacking the Chat
gene in the DMH, exposure to warm temperature reduces neither BAT Ucp1
DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMHACh
pathway may mediate physiological heat-defense responses to elevated environmental temperature. [Hide abstract]
Original Research ArticleObesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathyLalage A. Katunga, Preeti Gudimella, Jimmy T. Efird, Scott Abernathy, Taylor A. Mattox, Cherese Beatty, Timothy M. Darden, Kathleen A. Thayne, Hazaim Alwair, Alan P. Kypson, Jitka A. Virag, Ethan J. Anderson Abstract
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Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4
gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4
haploinsufficient mice (GPx4+/-
) and in samples of human myocardium.
Wild-type (WT) and GPx4+/-
mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.
Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4
) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4+/-
mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4+/-
but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.
These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure. [Hide abstract]
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