Publications by authors named "Sabrina Diano"

90 Publications

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior.

Mol Psychiatry 2021 Apr 20. Epub 2021 Apr 20.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.

Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain, but the mechanisms involved in the regulation of this process are ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglia-synapse contacts and an elevated amount of microglial phagocytic inclusions. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and a concurrent increase in expression of uncoupling protein 2 (Ucp2), a regulator of mitochondrial ROS generation. Conditional ablation of Ucp2 from microglia hindered phasic elimination of spine synapses with consequent accumulations of ROS and lysosome-lipid droplet complexes, which resulted in hippocampal neuronal circuit dysfunctions assessed by electrophysiology, and altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in the control of brain functions.
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http://dx.doi.org/10.1038/s41380-021-01105-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056795PMC
April 2021

Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism.

Nat Commun 2021 04 20;12(1):2330. Epub 2021 Apr 20.

Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.
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http://dx.doi.org/10.1038/s41467-021-22431-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058102PMC
April 2021

Drp1 is required for AgRP neuronal activity and feeding.

Elife 2021 Mar 9;10. Epub 2021 Mar 9.

Institute of Human Nutrition, Columbia University Irving Medical Center, New York, United States.

The hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons are crucial for the regulation of whole-body energy homeostasis. Here, we show that fasting-induced AgRP neuronal activation is associated with dynamin-related peptide 1 (DRP1)-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking in adult AgRP neurons (Drp1 cKO) show decreased fasting- or ghrelin-induced AgRP neuronal activity and feeding and exhibited a significant decrease in body weight, fat mass, and feeding accompanied by a significant increase in energy expenditure. In support of the role for mitochondrial fission and fatty acids oxidation, Drp1 cKO mice showed attenuated palmitic acid-induced mitochondrial respiration. Altogether, our data revealed that mitochondrial dynamics and fatty acids oxidation in hypothalamic AgRP neurons is a critical mechanism for AgRP neuronal function and body-weight regulation.
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http://dx.doi.org/10.7554/eLife.64351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946429PMC
March 2021

POMC neuronal heterogeneity in energy balance and beyond: an integrated view.

Nat Metab 2021 03 25;3(3):299-308. Epub 2021 Feb 25.

University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, INSERM U1215, Bordeaux, France.

Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body's energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons' functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.
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http://dx.doi.org/10.1038/s42255-021-00345-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085907PMC
March 2021

Hypothalamic glucose-sensing mechanisms.

Diabetologia 2021 May 5;64(5):985-993. Epub 2021 Feb 5.

Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Chronic metabolic diseases, including diabetes and obesity, have become a major global health threat of the twenty-first century. Maintaining glucose homeostasis is essential for survival in mammals. Complex and highly coordinated interactions between glucose-sensing mechanisms and multiple effector systems are essential for controlling glucose levels in the blood. The central nervous system (CNS) plays a crucial role in regulating glucose homeostasis. Growing evidence indicates that disruption of glucose sensing in selective CNS areas, such as the hypothalamus, is closely interlinked with the pathogenesis of obesity and type 2 diabetes mellitus. However, the underlying intracellular mechanisms of glucose sensing in the hypothalamus remain elusive. Here, we review the current literature on hypothalamic glucose-sensing mechanisms and discuss the impact of alterations of these mechanisms on the pathogenesis of diabetes.
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http://dx.doi.org/10.1007/s00125-021-05395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087998PMC
May 2021

MCR Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression.

Cell Rep 2020 10;33(2):108267

Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Program of Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Major depressive disorder is associated with weight loss and decreased appetite; however, the signaling that connects these conditions is unclear. Here, we show that MCR signaling in the dorsal raphe nucleus (DRN) affects feeding, anxiety, and depression. DRN infusion of α-MSH decreases DRN neuronal activation and feeding. DRN MCR is expressed in GABAergic PRCP-producing neurons. DRN selective knockdown of PRCP (Prcp), an enzyme inactivating α-MSH, decreases feeding and DRN neuronal activation. Interestingly, Prcp mice present lower DRN serotonin levels and depressive-like behavior. Similarly, PRCP-ablated MCR mice (Prcp) show metabolic and behavioral phenotypes comparable to those of Prcp mice. Selective PRCP re-expression in DRN MCR neurons of Prcp mice partially reverses feeding, while fully restoring mood behaviors. Chemogenetic inhibition of DRN MCR neurons induces anxiety, depression, and reduced feeding, whereas chemogenetic activation reverses these effects. Our results indicate that MCR signaling in DRN plays a role in feeding, anxiety, and depression.
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http://dx.doi.org/10.1016/j.celrep.2020.108267DOI Listing
October 2020

A Sympathetic Treatment for Obesity.

Cell Metab 2020 06;31(6):1043-1045

Program in Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Amphetamine (AMPH), mainly used in the treatment of attention deficit hyperactivity disorder and narcolepsy, has weight loss properties, although with detrimental cardiovascular effects. In this issue, Mahú et al. (2020) describe the effect of a new derivative of AMPH, "PEGyAMPH," a brain-spared anti-obesity drug that alters sympathetic activity without cardiovascular side effects.
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http://dx.doi.org/10.1016/j.cmet.2020.05.009DOI Listing
June 2020

Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform.

Nat Commun 2020 01 17;11(1):342. Epub 2020 Jan 17.

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06510, USA.

Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis. HNF4α functions to stimulate transcription of key gluconeogenic genes. HNF4α harbors two promoters (P2 and P1) thought to be primarily active in fetal and adult livers, respectively. Here we report that the fetal version of HNF4α is required for HGP in the adult liver. This isoform is acutely induced upon fasting and chronically increased in type-2 diabetes (T2D). P2 isoform induction occurs in response to glucagon-stimulated upregulation of TET3, not previously shown to be involved in HGP. TET3 is recruited to the P2 promoter by FOXA2, leading to promoter demethylation and increased transcription. While TET3 overexpression augments HGP, knockdown of either TET3 or the P2 isoform alone in the liver improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies unmask an unanticipated, conserved regulatory mechanism in HGP and offer potential therapeutic targets for T2D.
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http://dx.doi.org/10.1038/s41467-019-14185-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969024PMC
January 2020

Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding.

Cell Metab 2019 11 5;30(5):952-962.e5. Epub 2019 Sep 5.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples 80131, Italy. Electronic address:

Microglia play a crucial role in immune responses, including inflammation. Diet-induced obesity (DIO) triggers microglia activation and hypothalamic inflammation as early as 3 days after high-fat diet (HFD) exposure, before changes in body weight occur. The intracellular mechanism(s) responsible for HFD-induced microglia activation is ill defined. Here, we show that in vivo, HFD induced a rapid and transient increase in uncoupling protein 2 (Ucp2) mRNA expression together with changes in mitochondrial dynamics. Selective microglial deletion of Ucp2 prevented changes in mitochondrial dynamics and function, microglia activation, and hypothalamic inflammation. In association with these, male and female mice were protected from HFD-induced obesity, showing decreased feeding and increased energy expenditure that were associated with changes in the synaptic input organization and activation of the anorexigenic hypothalamic POMC neurons and astrogliosis. Together, our data point to a fuel-availability-driven mitochondrial mechanism as a major player of microglia activation in the central regulation of DIO.
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http://dx.doi.org/10.1016/j.cmet.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251564PMC
November 2019

Aromatase and estrogen receptor immunoreactivity in the coronary arteries of monkeys and human subjects.

Menopause 2018 11;25(11):1201-1207

Department of Obstetrics and Gynecology and Center for Research in Reproductive Biology, Yale University, New Haven, Connecticut.

Objective: The objective of this study was to determine whether estrogen could be formed locally in the coronary arteries.

Design: Coronary arteries were examined from monkeys (Macaca fascicularis, one male and one female) and human subjects (one premenopausal woman, one postmenopausal woman, and one man) by immunocytochemistry, using purified antisera against human placental estrogen synthetase (aromatase) and ER α. The arteries were graded for the amount of atherosclerosis.

Results: There was clear immunopositivity for both aromatase and estrogen receptors in all arteries studied. Although all endothelial cells (CD31 positive) stained for both antigens, the staining in macrophages, fibroblasts, and smooth muscle cells was irregular.

Conclusion: The present results provide the first evidence for the local formation of estrogen in the coronary arteries. In addition to complementing the evidence of a cardioprotective effect of estrogen on the coronary circulation, our results highlight the potential importance of local regulation of estrogen formation and the role of available precursor androgens in maintaining the cardiovascular system.
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http://dx.doi.org/10.1097/GME.0000000000001219DOI Listing
November 2018

Overexpression of melanocortin 2 receptor accessory protein 2 (MRAP2) in adult paraventricular MC4R neurons regulates energy intake and expenditure.

Mol Metab 2018 12 4;18:79-87. Epub 2018 Oct 4.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address:

Objective: Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons responsible for the phenotype of gross obesity in MRAP2 deficient animals are unclear. Furthermore, to date, all the murine MRAP2 models involve the prenatal deletion of MRAP2.

Methods: To target Melanocortin 4 receptor (MC4R)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), we performed stereotaxic surgery using AAV to selectively overexpress MRAP2 postnatally in adult Mc4r-cre mice. We assessed energy homeostasis, glucose metabolism, core body temperature, and response to MC3R/MC4R agonist MTII.

Results: Mc4r-cre female mice on a standard chow diet had less age-related weight gain and improved glucose/insulin profile compared to control Mc4r-cre mice. These changes were associated with a reduction in food intake and increased energy expenditure. In contrast, Mc4r-cre male mice showed no improvement on a chow diet, but improvement of energy and glucose metabolism was observed following high fat diet (HFD) feeding. In addition, an increase in core body temperature was found in both females fed on standard chow diet and males fed on HFD. Mc4r-cre female and male mice showed increased neuronal activation in the PVN compared to controls, with further increase in neuronal activation post MTII treatment in females.

Conclusions: Our data indicate a site-specific role for MRAP2 in PVN MC4R-expressing neurons in potentiating MC4R neuronal activation at baseline conditions in the regulation of food intake and energy expenditure.
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http://dx.doi.org/10.1016/j.molmet.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308034PMC
December 2018

Mitochondrial Dynamics and Hypothalamic Regulation of Metabolism.

Endocrinology 2018 10;159(10):3596-3604

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut.

Mitochondria are cellular organelles that play an important role in bioenergetic processes. In the central nervous system, high energy-demanding neurons are critically dependent on mitochondria to fulfill their appropriate functions. The hypothalamus is a key brain area for maintaining glucose and energy homeostasis via the ability of hypothalamic neurons to sense, integrate, and respond to numerous metabolic signals. Mitochondrial function has emerged as an important component in the regulation of hypothalamic neurons controlling glucose and energy homeostasis. Although the underlying mechanisms are not fully understood, emerging evidence indicates that mitochondrial dysfunction in hypothalamic neurons may contribute to the development of various metabolic diseases, including obesity and type 2 diabetes mellitus (T2DM). In this review, we summarize recent studies demonstrating the link between mitochondria and hypothalamic neural control of glucose and energy homeostasis. Finally, this review provides an insight to understand how mitochondria in hypothalamic neurons may contribute to the development of metabolic disorders, such as T2DM and obesity.
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http://dx.doi.org/10.1210/en.2018-00667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157417PMC
October 2018

A new brain circuit in feeding control.

Authors:
Sabrina Diano

Science 2018 07;361(6397):29-30

Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Comparative Medicine, and Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street FMB302A, New Haven, CT 06520, USA.

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http://dx.doi.org/10.1126/science.aau1419DOI Listing
July 2018

Prolyl carboxypeptidase in Agouti-related Peptide neurons modulates food intake and body weight.

Mol Metab 2018 04 8;10:28-38. Epub 2018 Feb 8.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06520, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address:

Objective: Prolyl carboxypeptidase (PRCP) plays a role in the regulation of energy metabolism by inactivating hypothalamic α-melanocyte stimulating hormone (α-MSH) levels. Although detected in the arcuate nucleus, limited PRCP expression has been observed in the arcuate POMC neurons, and its site of action in regulating metabolism is still ill-defined.

Methods: We performed immunostaining to assess the localization of PRCP in arcuate Neuropeptide Y/Agouti-related Peptide (NPY/AgRP) neurons. Hypothalamic explants were then used to assess the intracellular localization of PRCP and its release at the synaptic levels. Finally, we generated a mouse model to assess the role of PRCP in NPY/AgRP neurons of the arcuate nucleus in the regulation of metabolism.

Results: Here we show that PRCP is expressed in NPY/AgRP-expressing neurons of the arcuate nucleus. In hypothalamic explants, stimulation by ghrelin increased PRCP concentration in the medium and decreased PRCP content in synaptic extract, suggesting that PRCP is released at the synaptic level. In support of this, hypothalamic explants from mice with selective deletion of PRCP in AgRP neurons (Prcp) showed reduced ghrelin-induced PRCP concentration in the medium compared to controls mice. Furthermore, male Prcp mice had decreased body weight and fat mass compared to controls. However, this phenotype was sex-specific as female Prcp mice show metabolic differences only when challenged by high fat diet feeding. The improved metabolism of Prcp mice was associated with reduced food intake and increased energy expenditure, locomotor activity, and hypothalamic α-MSH levels. Administration of SHU9119, a potent melanocortin receptor antagonist, selectively in the PVN of Prcp male mice increased food intake to a level similar to that of control mice.

Conclusions: Altogether, our data indicate that PRCP is released at the synaptic levels and that PRCP in AgRP neurons contributes to the modulation of α-MSH degradation and related metabolic control in mice.
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http://dx.doi.org/10.1016/j.molmet.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985234PMC
April 2018

Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons.

Elife 2017 08 1;6. Epub 2017 Aug 1.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, United States.

POMC neurons integrate metabolic signals from the periphery. Here, we show in mice that food deprivation induces a linear current-voltage relationship of AMPAR-mediated excitatory postsynaptic currents (EPSCs) in POMC neurons. Inhibition of EPSCs by IEM-1460, an antagonist of calcium-permeable (Cp) AMPARs, diminished EPSC amplitude in the fed but not in the fasted state, suggesting entry of GluR2 subunits into the AMPA receptor complex during food deprivation. Accordingly, removal of extracellular calcium from ACSF decreased the amplitude of mEPSCs in the fed but not the fasted state. Ten days of high-fat diet exposure, which was accompanied by elevated leptin levels and increased POMC neuronal activity, resulted in increased expression of Cp-AMPARs on POMC neurons. Altogether, our results show that entry of calcium via Cp-AMPARs is inherent to activation of POMC neurons, which may underlie a vulnerability of these neurons to calcium overload while activated in a sustained manner during over-nutrition.
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http://dx.doi.org/10.7554/eLife.25755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538821PMC
August 2017

Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity.

Diabetes 2017 08 26;66(8):2102-2111. Epub 2017 May 26.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT

The Lin28a/ axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress ( ) or downregulate ( ) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in or mice. On a high-fat diet, although no differences in body weight and composition were observed, mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese or mice were not associated with alterations in levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1-dependent role for central Lin28a in glucose homeostasis.
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http://dx.doi.org/10.2337/db16-1558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521863PMC
August 2017

POMC Neurons: From Birth to Death.

Annu Rev Physiol 2017 02;79:209-236

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520; email:

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.
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http://dx.doi.org/10.1146/annurev-physiol-022516-034110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669621PMC
February 2017

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.

Cell Metab 2017 03 9;25(3):647-660. Epub 2017 Feb 9.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1-POMC-cre:ER) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1-POMC-cre:ER mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.
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http://dx.doi.org/10.1016/j.cmet.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366041PMC
March 2017

Hypothalamic and pituitary expression of ghrelin receptor message is increased during lactation.

Neurosci Lett 2016 Sep 15;631:126. Epub 2016 Sep 15.

Yale University School of Medicine, Department of Gynecology and Obstetrics, New Haven, CT, USA.

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http://dx.doi.org/10.1016/j.neulet.2016.07.025DOI Listing
September 2016

UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness.

Cell 2016 Feb;164(5):872-83

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, Yale University, New Haven, Connecticut 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut 06520, USA; Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, Connecticut 06520, USA; Section of Comparative Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut 06520, USA. Electronic address:

The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill defined. Here, we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH and that this process regulates systemic glucose homeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis.
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http://dx.doi.org/10.1016/j.cell.2016.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770556PMC
February 2016

Women in Metabolism: Part 3.

Cell Metab 2015 Dec;22(6):949-53

The "Rosies" of Cell Metabolism are back for the third part of the "Women in Metabolism" 2015 series. We are closing our anniversary celebrations with 14 inspiring and engaging new stories from women scientists in the metabolism field. A round of applause to all who contributed and supported this project!
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http://dx.doi.org/10.1016/j.cmet.2015.11.005DOI Listing
December 2015

AgRP Neurons Regulate Bone Mass.

Cell Rep 2015 Oct 24;13(1):8-14. Epub 2015 Sep 24.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1(-/-)), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1(-/-) mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.
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http://dx.doi.org/10.1016/j.celrep.2015.08.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868421PMC
October 2015

Prolyl Endopeptidase (PREP) is Associated With Male Reproductive Functions and Gamete Physiology in Mice.

J Cell Physiol 2016 Mar 18;231(3):551-7. Epub 2015 Sep 18.

Departments of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Yale University, New Haven, Connecticut.

Prolyl endopeptidase (PREP) is a serine protease which has been implicated in many biological processes, such as the maturation and degradation of peptide hormones and neuropeptides, learning and memory, cell proliferation and differentiation, and glucose metabolism. A small number of reports have also suggested PREP participation in both male and female reproduction-associated processes. In the present work, we examined PREP distribution in male germ cells and studied the effects of its knockdown (Prep(gt/gt)) on testis and sperm in adult mice. The protein is expressed and localized in elongating spermatids and luminal spermatozoa of wild type (wt) mice, as well as Sertoli, Leydig, and peritubular cells. PREP is also expressed in the head and midpiece of epididymal spermatozoa, whereas the remaining tail region shows a weaker signal. Furthermore, testis weight, histology of seminiferous tubules, and epididymal sperm parameters were assessed in wt and Prep(gt/gt) mice: wild type testes have larger average tubule and lumen diameter; in addition, lumenal composition of seminiferous tubules is dissimilar between wt and Prep(gt/gt), as the percentage of spermiated tubules is much higher in wt. Finally, total sperm count, sperm motility, and normal morphology are also higher in wt than in Prep(gt/gt). These results show for the first time that the expression of PREP could be necessary for a correct reproductive function, and suggest that the enzyme may play a role in mouse spermatogenesis and sperm physiology.
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http://dx.doi.org/10.1002/jcp.25178DOI Listing
March 2016

Hypothalamic POMC neurons promote cannabinoid-induced feeding.

Nature 2015 Mar 18;519(7541):45-50. Epub 2015 Feb 18.

1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB1R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.
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http://dx.doi.org/10.1038/nature14260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496586PMC
March 2015

Hormonal regulation of the hypothalamic melanocortin system.

Front Physiol 2014 9;5:480. Epub 2014 Dec 9.

Departments of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine New Haven, CT, USA ; Program in Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine New Haven, CT, USA ; Department of Neurobiology, Yale University School of Medicine New Haven, CT, USA ; Section of Comparative Medicine, Yale University School of Medicine New Haven, CT, USA.

Regulation of energy homeostasis is fundamental for life. In animal species and humans, the Central Nervous System (CNS) plays a critical role in such regulation by integrating peripheral signals and modulating behavior and the activity of peripheral organs. A precise interplay between CNS and peripheral signals is necessary for the regulation of food intake and energy expenditure in the maintenance of energy balance. Within the CNS, the hypothalamus is a critical center for monitoring, processing and responding to peripheral signals, including hormones such as ghrelin, leptin, and insulin. Once in the brain, peripheral signals regulate neuronal systems involved in the modulation of energy homeostasis. The main hypothalamic neuronal circuit in the regulation of energy metabolism is the melanocortin system. This review will give a summary of the most recent discoveries on the hormonal regulation of the hypothalamic melanocortin system in the control of energy homeostasis.
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http://dx.doi.org/10.3389/fphys.2014.00480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260486PMC
December 2014

Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex.

Int J Neuropsychopharmacol 2014 Oct 31;18(6). Epub 2014 Oct 31.

Neuropsychopharmacology Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Drs Elsworth, Groman, Redmond, and Roth); Department of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California (Dr Jentsch); Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut (Drs Leranth, Kim, and Diano).

Background: Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits.

Methods: The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys.

Results: One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance.

Conclusions: As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia.
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http://dx.doi.org/10.1093/ijnp/pyu048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438537PMC
October 2014

Mitochondrial UCP2 in the central regulation of metabolism.

Best Pract Res Clin Endocrinol Metab 2014 Oct 7;28(5):757-64. Epub 2014 Mar 7.

Departments of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Program in Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which uncouples the oxidative phosphorylation from ATP production by dissipating the proton gradient generated across the mitochondrial inner membrane. UCP2 regulates not only mitochondrial ATP production, but also the generation of reactive oxygen species (ROS), considered important second-messenger signals within the cell. The importance of UCP2 was firstly reported in macrophages and pancreatic beta cells. However, several studies have revealed the important role of UCP2 in the Central Nervous System (CNS) in the regulation of homeostatic mechanisms including food intake, energy expenditure, glucose homeostasis and reward behaviors. The mechanisms by which central UCP2 affect these processes seem to be associated with synaptic and mitochondrial plasticity. In this review, we will describe recent findings on central UCP2 and discuss its role in CNS regulation of homeostasis.
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http://dx.doi.org/10.1016/j.beem.2014.02.006DOI Listing
October 2014

PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding.

J Clin Invest 2014 Sep 1;124(9):4017-27. Epub 2014 Aug 1.

Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.
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http://dx.doi.org/10.1172/JCI76220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151211PMC
September 2014

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice.

Proc Natl Acad Sci U S A 2014 Aug 28;111(32):11876-81. Epub 2014 Jul 28.

Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism,Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520;Neurobiology,

Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prep(gt/gt)) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/gt) mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus-PREP reversed the glucose-intolerant phenotype of the Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.
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http://dx.doi.org/10.1073/pnas.1406000111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136568PMC
August 2014