Publications by authors named "Oksana Gavrilova"

133 Publications

Activation of neuronal adenosine A1 receptors causes hypothermia through central and peripheral mechanisms.

PLoS One 2020 16;15(12):e0243986. Epub 2020 Dec 16.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, United States of America.

Extracellular adenosine, a danger signal, can cause hypothermia. We generated mice lacking neuronal adenosine A1 receptors (A1AR, encoded by the Adora1 gene) to examine the contribution of these receptors to hypothermia. Intracerebroventricular injection of the selective A1AR agonist (Cl-ENBA, 5'-chloro-5'-deoxy-N6-endo-norbornyladenosine) produced hypothermia, which was reduced in mice with deletion of A1AR in neurons. A non-brain penetrant A1AR agonist [SPA, N6-(p-sulfophenyl) adenosine] also caused hypothermia, in wild type but not mice lacking neuronal A1AR, suggesting that peripheral neuronal A1AR can also cause hypothermia. Mice expressing Cre recombinase from the Adora1 locus were generated to investigate the role of specific cell populations in body temperature regulation. Chemogenetic activation of Adora1-Cre-expressing cells in the preoptic area did not change body temperature. In contrast, activation of Adora1-Cre-expressing dorsomedial hypothalamus cells increased core body temperature, concordant with agonism at the endogenous inhibitory A1AR causing hypothermia. These results suggest that A1AR agonism causes hypothermia via two distinct mechanisms: brain neuronal A1AR and A1AR on neurons outside the blood-brain barrier. The variety of mechanisms that adenosine can use to induce hypothermia underscores the importance of hypothermia in the mouse response to major metabolic stress or injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243986PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743955PMC
February 2021

Lack of adipocyte purinergic P2Y receptor greatly improves whole body glucose homeostasis.

Proc Natl Acad Sci U S A 2020 12 16;117(48):30763-30774. Epub 2020 Nov 16.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892;

Uridine diphosphate (UDP)-activated purinergic receptor P2Y (P2YR) plays a crucial role in controlling energy balance through central mechanisms. However, P2YR's roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2YR protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2YR deletion in skeletal muscle reduced glucose uptake, resulting in impaired glucose homeostasis. Interestingly, whole body P2YR knockout mice showed metabolic improvements similar to those observed with mice lacking P2YR only in adipocytes. Our findings provide compelling evidence that P2YR antagonists may prove useful for the treatment of obesity and type 2 diabetes.
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http://dx.doi.org/10.1073/pnas.2006578117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720204PMC
December 2020

Gα/Gα deficiency in dorsomedial hypothalamus leads to obesity resulting from decreased energy expenditure and impaired sympathetic nerve activity.

Am J Physiol Endocrinol Metab 2021 02 9;320(2):E270-E280. Epub 2020 Nov 9.

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

The G-protein subunits Gα and Gα (Gα) couple receptors to phospholipase C, leading to increased intracellular calcium. In this study we investigated the consequences of G/α deficiency in the dorsomedial hypothalamus (DMH), a critical site for the control of energy homeostasis. Mice with DMH-specific deletion of Gα (DMHGq/11KO) were generated by stereotaxic injection of adeno-associated virus (AAV)-Cre-green fluorescent protein (GFP) into the DMH of Gα:Gα mice. Compared with control mice that received DMH injection of AAV-GFP, DMHGq/11KO mice developed obesity associated with reduced energy expenditure without significant changes in food intake or physical activity. DMHGq/11KO mice showed no defects in the ability of the melanocortin agonist melanotan II to acutely stimulate energy expenditure or to inhibit food intake. At room temperature (22°C), DMHGq/11KO mice showed reduced sympathetic nervous system activity in brown adipose tissue (BAT) and heart, accompanied with decreased basal BAT uncoupling protein 1 () gene expression and lower heart rates. These mice were cold intolerant when acutely exposed to cold (6°C for 5 h) and had decreased cold-stimulated BAT gene expression. DMHGq/11KO mice also failed to adapt to gradually declining ambient temperatures and to develop adipocyte browning in inguinal white adipose tissue although their BAT was proportionally stimulated. Consistent with impaired cold-induced thermogenesis, the onset of obesity in DMHGq/11KO mice was significantly delayed when housed under thermoneutral conditions (30°C). Thus our results show that Gα and Gα in the DMH are required for the control of energy homeostasis by stimulating energy expenditure and thermoregulation. This paper demonstrates that signaling within the dorsomedial hypothalamus via the G proteins Gα and Gα, which couple cell surface receptors to the stimulation of phospholipase C, is critical for regulation of energy expenditure, thermoregulation by brown adipose tissue and the induction of white adipose tissue browning.
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http://dx.doi.org/10.1152/ajpendo.00059.2020DOI Listing
February 2021

17-Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury.

Hepatology 2020 Aug 11. Epub 2020 Aug 11.

Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Background And Aims: 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD-associated and alcohol-associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model.

Approach And Results: Single-cell RNA-sequencing and quantitative RT-PCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type (WT) littermate controls fed regular chow (RC), a high-fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation-related and fibrosis-related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets.

Conclusions: Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions did not reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies.
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http://dx.doi.org/10.1002/hep.31517DOI Listing
August 2020

The contribution of the mouse tail to thermoregulation is modest.

Am J Physiol Endocrinol Metab 2020 08 21;319(2):E438-E446. Epub 2020 Jul 21.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Understanding mouse thermal physiology informs the usefulness of mice as models of human disease. It is widely assumed that the mouse tail contributes greatly to heat loss (as it does in rat), but this has not been quantitated. We studied C57BL/6J mice after tail amputation. Tailless mice housed at 22°C did not differ from littermate controls in body weight, lean or fat content, or energy expenditure. With acute changes in ambient temperature from 19 to 39°C, tailless and control mice demonstrated similar body temperatures (Tb), metabolic rates, and heat conductances and no difference in thermoneutral point. Treatment with prazosin, an α1-adrenergic antagonist and vasodilator, increased tail temperature in control mice by up to 4.8 ± 0.8°C. Comparing prazosin treatment in tailless and control mice suggested that the tail's contribution to total heat loss was a nonsignificant 3.4%. Major heat stress produced by treatment at 30°C with CL316243, a β3-adrenergic agonist, increased metabolic rate and Tb and, at a matched increase in metabolic rate, the tailless mice showed a 0.72 ± 0.14°C greater Tb increase and 7.6% lower whole body heat conductance. Thus, the mouse tail is a useful biomarker of vasodilation and thermoregulation, but in our experiments contributes only 5-8% of whole body heat dissipation, less than the 17% reported for rat. Heat dissipation through the tail is important under extreme scenarios such as pharmacological activation of brown adipose tissue; however, non-tail contributions to heat loss may have been underestimated in the mouse.
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http://dx.doi.org/10.1152/ajpendo.00133.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473913PMC
August 2020

β-arrestin-1 suppresses myogenic reprogramming of brown fat to maintain euglycemia.

Sci Adv 2020 Jun 5;6(23):eaba1733. Epub 2020 Jun 5.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.

A better understanding of the signaling pathways regulating adipocyte function is required for the development of new classes of antidiabetic/obesity drugs. We here report that mice lacking β-arrestin-1 (barr1), a cytoplasmic and nuclear signaling protein, selectively in adipocytes showed greatly impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet. In contrast, transgenic mice overexpressing barr1 in adipocytes were protected against the metabolic deficits caused by a high-calorie diet. Barr1 deficiency led to a myogenic reprogramming of brown adipose tissue (BAT), causing elevated plasma myostatin (Mstn) levels, which in turn led to impaired insulin signaling in multiple peripheral tissues. Additional in vivo studies indicated that barr1-mediated suppression of Mstn expression by BAT is required for maintaining euglycemia. These findings convincingly identify barr1 as a critical regulator of BAT function. Strategies aimed at enhancing barr1 activity in BAT may prove beneficial for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1126/sciadv.aba1733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274797PMC
June 2020

Beneficial metabolic role of β-arrestin-1 expressed by AgRP neurons.

Sci Adv 2020 Jun 3;6(23):eaaz1341. Epub 2020 Jun 3.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.

β-Arrestin-1 and β-arrestin-2 have emerged as important signaling molecules that modulate glucose fluxes in several peripheral tissues. The potential roles of neuronally expressed β-arrestins in regulating glucose homeostasis remain unknown. We here report that mice lacking β-arrestin-1 (barr1) selectively in AgRP neurons displayed impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet, while mice overexpressing barr1 selectively in AgRP neurons were protected against obesity-associated metabolic impairments. Additional physiological, biochemical, and electrophysiological data indicated that the presence of barr1 is essential for insulin-mediated hyperpolarization of AgRP neurons. As a result, barr1 expressed by AgRP neurons regulates efferent neuronal pathways that suppress hepatic glucose production and promote lipolysis in adipose tissue. Mice lacking β-arrestin-2 (barr2) selectively in AgRP neurons showed no substantial metabolic phenotypes. Our data suggest that agents able to enhance the activity of barr1 in AgRP neurons may prove beneficial as antidiabetic drugs.
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http://dx.doi.org/10.1126/sciadv.aaz1341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269658PMC
June 2020

Adipocyte G signaling is essential for maintaining whole-body glucose homeostasis and insulin sensitivity.

Nat Commun 2020 06 12;11(1):2995. Epub 2020 Jun 12.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.

Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes. Adipocyte function is regulated by receptor-mediated activation of heterotrimeric G proteins. Little is known about the potential in vivo metabolic roles of G-type G proteins expressed by adipocytes, primarily due to the lack of suitable animal models. To address this question, we generated mice lacking functional G proteins selectively in adipocytes. Here we report that these mutant mice displayed significantly impaired glucose tolerance and reduced insulin sensitivity when maintained on an obesogenic diet. In contrast, using a chemogenetic strategy, we demonstrated that activation of G signaling selectively in adipocytes greatly improved glucose homeostasis and insulin signaling. We also elucidated the cellular mechanisms underlying the observed metabolic phenotypes. Our data support the concept that adipocyte G signaling is essential for maintaining euglycemia. Drug-mediated activation of adipocyte G signaling may prove beneficial for restoring proper glucose homeostasis in type 2 diabetes.
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http://dx.doi.org/10.1038/s41467-020-16756-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293267PMC
June 2020

Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis.

Hepatology 2021 Mar 3;73(3):1176-1193. Epub 2020 Nov 3.

Genetics and Metabolism Section, NIDDK, NIH, Bethesda, MD.

Background And Aims: Iron is essential yet also highly chemically reactive and potentially toxic. The mechanisms that allow cells to use iron safely are not clear; defects in iron management are a causative factor in the cell-death pathway known as ferroptosis. Poly rC binding protein 1 (PCBP1) is a multifunctional protein that serves as a cytosolic iron chaperone, binding and transferring iron to recipient proteins in mammalian cells. Although PCBP1 distributes iron in cells, its role in managing iron in mammalian tissues remains open for study. The liver is highly specialized for iron uptake, utilization, storage, and secretion.

Approach And Results: Mice lacking PCBP1 in hepatocytes exhibited defects in liver iron homeostasis with low levels of liver iron, reduced activity of iron enzymes, and misregulation of the cell-autonomous iron regulatory system. These mice spontaneously developed liver disease with hepatic steatosis, inflammation, and degeneration. Transcriptome analysis indicated activation of lipid biosynthetic and oxidative-stress response pathways, including the antiferroptotic mediator, glutathione peroxidase type 4. Although PCBP1-deleted livers were iron deficient, dietary iron supplementation did not prevent steatosis; instead, dietary iron restriction and antioxidant therapy with vitamin E prevented liver disease. PCBP1-deleted hepatocytes exhibited increased labile iron and production of reactive oxygen species (ROS), were hypersensitive to iron and pro-oxidants, and accumulated oxidatively damaged lipids because of the reactivity of unchaperoned iron.

Conclusions: Unchaperoned iron in PCBP1-deleted mouse hepatocytes leads to production of ROS, resulting in lipid peroxidation (LPO) and steatosis in the absence of iron overload. The iron chaperone activity of PCBP1 is therefore critical for limiting the toxicity of cytosolic iron and may be a key factor in preventing the LPO that triggers the ferroptotic cell-death pathway.
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http://dx.doi.org/10.1002/hep.31328DOI Listing
March 2021

Novel metabolic role for BDNF in pancreatic β-cell insulin secretion.

Nat Commun 2020 04 23;11(1):1950. Epub 2020 Apr 23.

Mouse Cancer Genetics Program, CCR, NCI, NIH, Frederick, USA.

BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.T1 is expressed by pancreatic β-cells where it regulates insulin release. Mice lacking TrkB.T1 show impaired glucose tolerance and insulin secretion. β-cell BDNF-TrkB.T1 signaling triggers calcium release from intracellular stores, increasing glucose-induced insulin secretion. Additionally, BDNF is secreted by skeletal muscle and muscle-specific BDNF knockout phenocopies the β-cell TrkB.T1 deletion metabolic impairments. The finding that BDNF is also secreted by differentiated human muscle cells and induces insulin secretion in human islets via TrkB.T1 identifies a new regulatory function of BDNF on metabolism that is independent of CNS activity. Our data suggest that muscle-derived BDNF may be a key factor mediating increased glucose metabolism in response to exercise, with implications for the treatment of diabetes and related metabolic diseases.
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http://dx.doi.org/10.1038/s41467-020-15833-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181656PMC
April 2020

Mouse Thermoregulation: Introducing the Concept of the Thermoneutral Point.

Cell Rep 2020 04;31(2):107501

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

Human and mouse thermal physiology differ due to dissimilar body sizes. Unexpectedly, in mice we found no ambient temperature zone where both metabolic rate and body temperature were constant. Body temperature began increasing once cold-induced thermogenesis was no longer required. This result reproduced in male, female, C57BL/6J, 129, chow-fed, diet-induced obese, and ob/ob mice as well as Trpv1;Trpm8;Trpa1 mice lacking thermal sensory channels. During the resting-light phase, the energy expenditure minimum spanned ∼4°C of ambient temperature, whereas in the active-dark phase it approximated a point. We propose the concept of a thermoneutral point (TNP), a discrete ambient temperature below which energy expenditure increases and above which body temperature increases. Humans do not have a TNP. As studied, the mouse TNP is ∼29°C in light phase and ∼33°C in dark phase. These observations inform how thermoneutrality is defined and how mice are used to model human energy physiology and drug development.
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http://dx.doi.org/10.1016/j.celrep.2020.03.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243168PMC
April 2020

Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A Adenosine Receptors: Affinity Enhancement by -(2-Phenylethyl) Substitution.

J Med Chem 2020 04 9;63(8):4334-4348. Epub 2020 Apr 9.

Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.

Dopamine-derived -substituents, compared to -(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue (MRS7591, = 10.9/17.8 nM, at human/mouse AAR). was a partial agonist in vitro (hAAR, cAMP inhibition, 31% ; mAAR, [S]GTP-γ-S binding, 16% ) and in vivo and also antagonized hAAR in vitro. Distal H-bonding substitutions of the -(2-phenylethyl) moiety particularly enhanced mAAR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mAAR and hAAR homology models. These hybrid models were based on an inactive antagonist-bound hAAR structure for the upper part of TM2 and an agonist-bound hAAR structure for the remaining TM portions. These species-independent AAR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the AAR, a drug target of growing interest.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443318PMC
April 2020

BRS3 in both MC4R- and SIM1-expressing neurons regulates energy homeostasis in mice.

Mol Metab 2020 06 29;36:100969. Epub 2020 Feb 29.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

Objective: Bombesin-like receptor 3 (BRS3) is an orphan receptor and Brs3 knockout mice develop obesity with increased food intake and reduced resting metabolic rate and body temperature. The neuronal populations contributing to these effects were examined.

Methods: We studied energy metabolism in mice with Cre-mediated recombination causing 1) loss of BRS3 selectively in SIM1- or MC4R-expressing neurons or 2) selective re-expression of BRS3 from a null background in these neurons.

Results: The deletion of BRS3 in MC4R neurons increased body weight/adiposity, metabolic efficiency, and food intake, and reduced insulin sensitivity. BRS3 re-expression in these neurons caused partial or no reversal of these traits. However, these observations were confounded by an obesity phenotype caused by the Mc4r-Cre allele, independent of its recombinase activity. The deletion of BRS3 in SIM1 neurons increased body weight/adiposity and food intake, but not to the levels of the global null. The re-expression of BRS3 in SIM1 neurons reduced body weight/adiposity and food intake, but not to wild type levels. The deletion of BRS3 in either MC4R- or SIM1-expressing neurons affected body temperature, with re-expression in either population reversing the null phenotype. MK-5046, a BRS3 agonist, increases light phase body temperature in wild type, but not Brs3 null, mice and BRS3 re-expression in either population restored response to MK-5046.

Conclusions: BRS3 in both MC4R- and SIM1-expressing neurons contributes to regulation of body weight/adiposity, insulin sensitivity, food intake, and body temperature.
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http://dx.doi.org/10.1016/j.molmet.2020.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113433PMC
June 2020

Sex-specific brain erythropoietin regulation of mouse metabolism and hypothalamic inflammation.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Molecular Medicine Branch.

The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high-fat diet-induced (HFD-induced) obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive overexpression of human EPO solely in the brain (Tg21) were used to assess the neuroendocrine EPO effect without increasing the hematocrit. Male Tg21 mice resisted HFD-induced weight gain; showed lower serum adrenocorticotropic hormone, corticosterone, and C-reactive protein levels; and prevented myeloid cell recruitment to the hypothalamus compared with WT male mice. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21 male mice exhibited a lower increase in HI than WT male mice. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Female estrogen production blocked reduced weight gain and HI. Targeted deletion of EpoR gene expression in neuronal cells worsened HFD-induced glucose intolerance in both male and female mice but increased weight gain and HI in the hypothalamus in male mice only. Both male and female Tg21 mice kept on normal chow and HFD showed significantly improved glycemic control. Our data indicate that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.
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http://dx.doi.org/10.1172/jci.insight.134061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141393PMC
March 2020

Selective activation of G signaling in adipocytes causes striking metabolic improvements in mice.

Mol Metab 2019 09 20;27:83-91. Epub 2019 Jun 20.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA. Electronic address:

Objective: Given the worldwide epidemics of obesity and type 2 diabetes, novel antidiabetic and appetite-suppressing drugs are urgently needed. Adipocytes play a central role in the regulation of whole-body glucose and energy homeostasis. The goal of this study was to examine the metabolic effects of acute and chronic activation of G signaling selectively in adipocytes (activated G stimulates cAMP production), both in lean and obese mice.

Methods: To address this question, we generated a novel mutant mouse strain (adipo-GsD mice) that expressed a G-coupled designer G protein-coupled receptor (Gs DREADD or short GsD) selectively in adipocytes. Importantly, the GsD receptor can only be activated by administration of an exogenous agent (CNO) that is otherwise pharmacologically inert. The adipo-GsD mice were maintained on either regular chow or a high-fat diet and then subjected to a comprehensive series of metabolic tests.

Results: Pharmacological (CNO) activation of the GsD receptor in adipocytes of adipo-GsD mice caused profound improvements in glucose homeostasis and protected mice against the metabolic deficits associated with the consumption of a calorie-rich diet. Moreover, chronic activation of G signaling in adipocytes led to a striking increase in energy expenditure and reduced food intake, resulting in a decrease in body weight and fat mass when mice consumed a calorie-rich diet.

Conclusion: Systematic studies with a newly developed mouse model enabled us to assess the metabolic consequences caused by acute or chronic activation of G signaling selectively in adipocytes. Most strikingly, chronic activation of this pathway led to reduced body fat mass and restored normal glucose homeostasis in obese mice. These findings are of considerable relevance for the development of novel antidiabetic and anti-obesity drugs.
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http://dx.doi.org/10.1016/j.molmet.2019.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717953PMC
September 2019

Adipocyte β-arrestin-2 is essential for maintaining whole body glucose and energy homeostasis.

Nat Commun 2019 07 3;10(1):2936. Epub 2019 Jul 3.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, NIH-20892, USA.

β-Arrestins are major regulators of G protein-coupled receptor-mediated signaling processes. Their potential roles in regulating adipocyte function in vivo remain unexplored. Here we report the novel finding that mice lacking β-arrestin-2 (barr2) selectively in adipocytes show significantly reduced adiposity and striking metabolic improvements when consuming excess calories. We demonstrate that these beneficial metabolic effects are due to enhanced signaling through adipocyte β3-adrenergic receptors (β3-ARs), indicating that barr2 represents a potent negative regulator of adipocyte β3-AR activity in vivo. Interestingly, essentially all beneficial metabolic effects caused by adipocyte barr2 deficiency are absent in adipocyte barr2-PRDM16 double KO mice, indicating that the metabolic improvements caused by the lack of barr2 in adipocytes are mediated by the browning/beiging of white adipose tissue. Our data support the novel concept that 'G protein-biased' β3-AR agonists that do not promote β3-AR/barr2 interactions may prove useful for the treatment of obesity and related metabolic disorders.
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http://dx.doi.org/10.1038/s41467-019-11003-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610117PMC
July 2019

The Catalytic Subunit of PKA Affects Energy Balance and Catecholaminergic Activity.

J Endocr Soc 2019 May 28;3(5):1062-1078. Epub 2019 Mar 28.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

The protein kinase A (PKA) signaling system mediates the effects of numerous hormones, neurotransmitters, and other molecules to regulate metabolism, cardiac function, and more. PKA defects may lead to diverse phenotypes that largely depend on the unique expression profile of the affected subunit. Deletion of the gene, which codes for PKA catalytic subunit (C), protects against diet-induced obesity (DIO), yet the mechanism for this phenotype remains unclear. We hypothesized that metabolic rate would be increased in C knockout (KO) mice, which could explain DIO resistance. Male, but not female, CKO mice had increased energy expenditure, and female but not male CKO mice had increased subcutaneous temperature and increased locomotor activity compared with wild-type (WT) littermates. Urinary norepinephrine (NE) and normetanephrine were elevated in female CKO mice. CKO mice had increased heart rate (HR); blocking central NE release normalized HR to that of untreated WT mice. Basal and stimulated PKA enzymatic activities were unchanged in adipose tissue and heart and varied in different brain regions, suggesting that deletion may mediate signaling changes in specific brain nuclei and may be less important in the peripheral regulation of PKA expression and activity. This is a demonstration of a distinct effect of the PKA C catalytic subunit on catecholamines and sympathetic nerve signaling. The data provide an unexpected explanation for the metabolic phenotype of CKO mice. Finally, the sexual dimorphism is consistent with mouse models of other PKA subunits and adds to the importance of these findings regarding the PKA system in human metabolism.
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http://dx.doi.org/10.1210/js.2019-00029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503631PMC
May 2019

Macrophage derived TNFα promotes hepatic reprogramming to Warburg-like metabolism.

J Mol Med (Berl) 2019 09 3;97(9):1231-1243. Epub 2019 May 3.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Room 4A62, Bethesda, MD, 20892, USA.

During infection, hepatocytes must undergo a reprioritization of metabolism, termed metabolic reprogramming. Hepatic metabolic reprogramming in response to infection begins within hours of infection, suggesting a mechanism closely linked to pathogen recognition. Following injection with polyinosinic:polycytidylic acid, a mimic of viral infection, a robust hepatic innate immune response could be seen involving the TNFα pathway at 2 h. Repeated doses led to the adoption of Warburg-like metabolism in the liver as determined by in vivo metabolic imaging, expression analyses, and metabolomics. Hepatic macrophages, Kupffer cells, were able to induce Warburg-like metabolism in hepatocytes in vitro via TNFα. Eliminating macrophages in vivo or blocking TNFα in vitro or in vivo resulted in abrogation of the metabolic phenotype, establishing an immune-metabolic axis in hepatic metabolic reprogramming. Overall, we suggest that macrophages, as early sensors of pathogens, instruct hepatocytes via TNFα to undergo metabolic reprogramming to cope with challenges to homeostasis initiated by infection. This work not only addresses a key component of end-organ physiology, but also raises questions about the side effects of biologics in the treatment of inflammatory diseases. KEY MESSAGES: • Hepatocytes develop Warburg-like metabolism in vivo during viral infection. • Macrophage TNFα promotes expression of glycolytic enzymes in hepatocytes. • Blocking this immune-metabolic axis abrogates Warburg-like metabolism in the liver. • Implications for patients being treated for inflammatory diseases with biologics.
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http://dx.doi.org/10.1007/s00109-019-01786-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715514PMC
September 2019

Gα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling.

Mol Metab 2019 07 12;25:142-153. Epub 2019 Apr 12.

Metabolic Diseases Branch, Bethesda, MD, 20892, USA. Electronic address:

Objective: Gα couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating Gα mutations lead to obesity in humans and mice. Mice with brain-specific Gα deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear.

Methods: We created mice (DMHGsKO) with Gα deficiency limited to the dorsomedial hypothalamus (DMH) and examined the effects on energy balance and thermogenesis.

Results: DMHGsKO mice developed severe, early-onset obesity associated with hyperphagia and reduced energy expenditure and locomotor activity, along with impaired brown adipose tissue thermogenesis. Studies in mice with loss of MC4R in the DMH suggest that defective DMH MC4R/Gα signaling contributes to abnormal energy balance but not to abnormal locomotor activity or cold-induced thermogenesis. Instead, DMHGsKO mice had impaired leptin signaling along with increased expression of the leptin signaling inhibitor protein tyrosine phosphatase 1B in the DMH, which likely contributes to the observed hyperphagia and reductions in energy expenditure, locomotor activity, and cold-induced thermogenesis.

Conclusions: DMH Gα signaling is critical for energy balance, thermogenesis, and leptin signaling. This study provides insight into how distinct signaling pathways can interact to regulate energy homeostasis and temperature regulation.
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http://dx.doi.org/10.1016/j.molmet.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601467PMC
July 2019

Physiology and effects of nucleosides in mice lacking all four adenosine receptors.

PLoS Biol 2019 03 1;17(3):e3000161. Epub 2019 Mar 1.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, United States of America.

Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1-/-;Adora2a-/-;Adora2b-/-;Adora3-/- (quad knockout [QKO]), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5'-monophosphate (AMP)-induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature.
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http://dx.doi.org/10.1371/journal.pbio.3000161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415873PMC
March 2019

Design and in Vivo Characterization of A Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series.

J Med Chem 2019 02 3;62(3):1502-1522. Epub 2019 Jan 3.

School of Pharmacy , Queen's University Belfast , 96 Lisburn Road , Belfast BT9 7BL , U.K.

(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A adenosine receptor (AAR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's AAR compatibility. N-Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for AAR) and known truncated N-dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hAAR selectivity. Methanocarba modification reduced AAR selectivity of N-dicyclopropylmethyl and endo-norbornyladenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mAAR full agonism and variable mAAR efficacy, but strong hypothermia by 9 depended on AAR, which reflects CNS activity (determined using AAR or AAR null mice). Conserved hAAR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold AAR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with AAR-enhancing N-dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467784PMC
February 2019

Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake.

Nat Neurosci 2018 11 22;21(11):1530-1540. Epub 2018 Oct 22.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Bombesin-like receptor 3 (BRS3) is an orphan G-protein-coupled receptor that regulates energy homeostasis and heart rate. We report that acute activation of Brs3-expressing neurons in the dorsomedial hypothalamus (DMH) increased body temperature (Tb), brown adipose tissue temperature, energy expenditure, heart rate, and blood pressure, with no effect on food intake or physical activity. Conversely, activation of Brs3 neurons in the paraventricular nucleus of the hypothalamus had no effect on Tb or energy expenditure, but suppressed food intake. Inhibition of DMH neurons decreased Tb and energy expenditure, suggesting a necessary role in Tb regulation. We found that the preoptic area provides major input (excitatory and inhibitory) to DMH neurons. Optogenetic stimulation of DMH projections to the raphe pallidus increased Tb. Thus, DMH→raphe pallidus neurons regulate Tb, energy expenditure, and heart rate, and Brs3 neurons in the paraventricular nucleus of the hypothalamus regulate food intake. Brs3 expression is a useful marker for delineating energy metabolism regulatory circuitry.
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http://dx.doi.org/10.1038/s41593-018-0249-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203600PMC
November 2018

Olfactomedin 4 Deletion Improves Male Mouse Glucose Intolerance and Insulin Resistance Induced by a High-Fat Diet.

Endocrinology 2018 09;159(9):3235-3244

Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Glucose-stimulated insulin secretion (GSIS) is essential for blood glucose homeostasis and is impaired in type 2 diabetes mellitus. Understanding the regulatory components of GSIS has clinical implications for diabetes treatment. In this study, we found that olfactomedin 4 (OLFM4) is endogenously expressed in pancreatic islet β cells and further investigated its potential roles in glucose homeostasis and the pathogenesis of type 2 diabetes using mouse models. Olfm4-deficient mice showed significantly improved glucose tolerance and significantly increased insulin levels after glucose challenge compared with wild-type (WT) mice. GSIS, mitochondrial ATP production, and mitochondrial respiration were all significantly increased in islets isolated from Olfm4-deficient mice compared with those isolated from WT mice. In a high-fat diet (HFD)-induced diabetic mouse model, the increase in insulin levels after glucose challenge was significantly higher in Olfm4-deficient mice compared with WT mice. The impaired glucose tolerance and insulin resistance in HFD-fed mice were improved by loss of Olfm4. Olfm4 was found to be mainly localized in the mitochondria and interacts with GRIM-19 (a gene associated with retinoid-interferon mortality) in Min6 pancreatic β cells. Collectively, these studies suggest that Olfm4 negatively regulates GSIS. OLFM4 may represent a potential therapeutic target for impaired glucose tolerance and patients with type 2 diabetes.
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http://dx.doi.org/10.1210/en.2018-00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098226PMC
September 2018

Melanotan II causes hypothermia in mice by activation of mast cells and stimulation of histamine 1 receptors.

Am J Physiol Endocrinol Metab 2018 09 29;315(3):E357-E366. Epub 2018 May 29.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.

Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in Kit mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner. In vitro, MTII stimulated mast cells by both MRGPRB2-dependent and -independent mechanisms, and MTII-induced hypothermia was intact in MRGPRB2-null mice. Confirming that MTII activated mast cells, MTII treatment increased plasma histamine levels in both wild-type and MRGPRB2-null, but not in Kit, mice. The released histamine produced hypothermia via histamine H receptors because either a selective antagonist, pyrilamine, or ablation of H receptors greatly diminished the hypothermia. Other drugs, including compound 48/80, a commonly used mast cell activator, also produced hypothermia by both mast cell-dependent and -independent mechanisms. These results suggest that mast cell activation should be considered when investigating the mechanism of drug-induced hypothermia in mice.
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http://dx.doi.org/10.1152/ajpendo.00024.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171009PMC
September 2018

The stimulatory G protein Gα is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis, and glucose metabolism.

J Biol Chem 2018 07 24;293(28):10993-11005. Epub 2018 May 24.

From the Metabolic Diseases Branch and

Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein Gα, but whether Gα mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous Gα-inactivating mutations, only develop obesity when the Gα mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates Gα imprinting within the central nervous system (CNS) in this disorder. In this study, we examined the effects of Gα in MC4R-expressing cells on metabolic regulation. Mice with homozygous Gα deficiency in MC4R-expressing cells (MC4RGsKO) developed significant obesity with increased food intake and decreased energy expenditure, along with impaired insulin sensitivity and cold-induced thermogenesis. Moreover, the ability of the MC4R agonist melanotan-II (MTII) to stimulate energy expenditure and to inhibit food intake was impaired in MC4RGsKO mice. MTII failed to stimulate the secretion of the anorexigenic hormone peptide YY (PYY) from enteroendocrine L cells, a physiological response mediated by MC4R-Gα signaling, even though baseline PYY levels were elevated in these mice. In Gα heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a Gα deletion on the maternal allele in MC4R-expressing cells, whereas food intake was unaffected. These results demonstrate that Gα signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that Gα imprinting in MC4R-expressing cells contributes to obesity in Gα knockout mice and probably in individuals with Albright hereditary osteodystrophy as well.
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http://dx.doi.org/10.1074/jbc.RA118.003450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052205PMC
July 2018

Depletion of Nsd2-mediated histone H3K36 methylation impairs adipose tissue development and function.

Nat Commun 2018 05 4;9(1):1796. Epub 2018 May 4.

Adipocyte Biology and Gene Regulation Section, LERB, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892, USA.

The epigenetic mechanisms regulating adipose tissue development and function are poorly understood. In this study, we show that depletion of histone H3K36 methylation by H3.3K36M in preadipocytes inhibits adipogenesis by increasing H3K27me3 to prevent the induction of C/EBPα and other targets of the master adipogenic transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). Depleting H3K36 methyltransferase Nsd2, but not Nsd1 or Setd2, phenocopies the effects of H3.3K36M on adipogenesis and PPARγ target expression. Consistently, expression of H3.3K36M in progenitor cells impairs brown adipose tissue (BAT) and muscle development in mice. In contrast, depletion of histone H3K36 methylation by H3.3K36M in adipocytes in vivo does not affect adipose tissue weight, but leads to profound whitening of BAT and insulin resistance in white adipose tissue (WAT). These mice are resistant to high fat diet-induced WAT expansion and show severe lipodystrophy. Together, these results suggest a critical role of Nsd2-mediated H3K36 methylation in adipose tissue development and function.
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http://dx.doi.org/10.1038/s41467-018-04127-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935725PMC
May 2018

Activation of adenosine A or A receptors causes hypothermia in mice.

Neuropharmacology 2018 09 13;139:268-278. Epub 2018 Mar 13.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

Extracellular adenosine is a danger/injury signal that initiates protective physiology, such as hypothermia. Adenosine has been shown to trigger hypothermia via agonism at A and A adenosine receptors (AAR, AAR). Here, we find that adenosine continues to elicit hypothermia in mice null for AAR and AAR and investigated the effect of agonism at AAR or AAR. The poorly brain penetrant AAR agonists CGS-21680 and PSB-0777 caused hypothermia, which was not seen in mice lacking AAR. MRS7352, a likely non-brain penetrant AAR antagonist, inhibited PSB-0777 hypothermia. While vasodilation is probably a contributory mechanism, AAR agonism also caused hypometabolism, indicating that vasodilation is not the sole mechanism. The AAR agonist BAY60-6583 elicited hypothermia, which was lost in mice null for AAR. Low intracerebroventricular doses of BAY60-6583 also caused hypothermia, indicating a brain site of action, with neuronal activation in the preoptic area and paraventricular nucleus of the hypothalamus. Thus, agonism at any one of the canonical adenosine receptors, AAR, AAR, AAR, or AAR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.
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http://dx.doi.org/10.1016/j.neuropharm.2018.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067974PMC
September 2018

Ablation of PPARγ in subcutaneous fat exacerbates age-associated obesity and metabolic decline.

Aging Cell 2018 04 31;17(2). Epub 2018 Jan 31.

Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA.

It is well established that aging is associated with metabolic dysfunction such as increased adiposity and impaired energy dissipation; however, the transcriptional mechanisms regulating energy balance during late life stages have not yet been fully elucidated. Here, we show that ablation of the nuclear receptor PPARγ specifically in inguinal fat tissue in aging mice is associated with increased fat tissue expansion and insulin resistance. These metabolic effects are accompanied by decreased thermogenesis, reduced levels of brown fat genes, and browning of subcutaneous adipose tissue. Comparative studies of the effects of PPARγ downregulation in young and mid-aged mice demonstrate a preferential regulation of brown fat gene programs in inguinal fat in an age-dependent manner. In conclusion, our study uncovers an essential role for PPARγ in maintaining energy expenditure during the aging process and suggests the possibility of targeting PPARγ to counteract age-associated metabolic dysfunction.
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http://dx.doi.org/10.1111/acel.12721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847881PMC
April 2018

Corrigendum to "Bombesin-like receptor 3 (Brs3) expression in glutamatergic, but not GABAergic, neurons is required for regulation of energy metabolism" [Mol Metabol 6 (2017) 1540-1550].

Mol Metab 2018 03 27;9:220. Epub 2017 Dec 27.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

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http://dx.doi.org/10.1016/j.molmet.2017.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869731PMC
March 2018