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Dive into the research topics where Kristin E. Claflin is active.

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Featured researches published by Kristin E. Claflin.


Molecular Therapy | 2012

Sialic Acid Deposition Impairs the Utility of AAV9, but Not Peptide-modified AAVs for Brain Gene Therapy in a Mouse Model of Lysosomal Storage Disease

Yong Hong Chen; Kristin E. Claflin; James Geoghegan; Beverly L. Davidson

Recombinant vector systems have been recently identified that when delivered systemically can transduce neurons, glia, and endothelia in the central nervous system (CNS), providing an opportunity to develop therapies for diseases affecting the brain without performing direct intracranial injections. Vector systems based on adeno-associated virus (AAV) include AAV serotype 9 (AAV9) and AAVs that have been re-engineered at the capsid level for CNS tropism. Here, we performed a head-to-head comparison of AAV9 and a capsid modified AAV for their abilities to rescue CNS and peripheral disease in an animal model of lysosomal storage disease (LSD), the mucopolysacharidoses (MPS) VII mouse. While the peptide-modified AAV reversed cognitive deficits, improved storage burden in the brain, and substantially prolonged survival, we were surprised to find that AAV9 provided no CNS benefit. Additional experiments demonstrated that sialic acid, a known inhibitor of AAV9, is elevated in the CNS of MPS VII mice. These studies highlight how disease manifestations can dramatically impact the known tropism of recombinant vectors, and raise awareness to assuming similar transduction profiles between normal and disease models.


Current Hypertension Reports | 2015

Control of Energy Balance by the Brain Renin-Angiotensin System

Kristin E. Claflin; Justin L. Grobe

The renin-angiotensin system (RAS) exists as a circulating hormone system but it is also used by various tissues of the body, including the brain, as a paracrine signaling mechanism. The local brain version of the RAS is mechanistically involved in fluid balance and blood pressure control, and there is growing appreciation for a role of the brain RAS in the control of energy balance. Here, we review major evidence for the control of energy balance by the brain RAS; outline the current understanding of the RAS components, targets, and mechanisms involved; and highlight some major questions that currently face the field.


Journal of Clinical Investigation | 2017

Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism

Kristin E. Claflin; Jeremy A. Sandgren; Allyn M. Lambertz; Benjamin J. Weidemann; Nicole K. Littlejohn; Colin M.L. Burnett; Nicole A. Pearson; Donald A. Morgan; Katherine N. Gibson-Corley; Kamal Rahmouni; Justin L. Grobe

Leptin contributes to the control of resting metabolic rate (RMR) and blood pressure (BP) through its actions in the arcuate nucleus (ARC). The renin-angiotensin system (RAS) and angiotensin AT1 receptors within the brain are also involved in the control of RMR and BP, but whether this regulation overlaps with leptin’s actions is unclear. Here, we have demonstrated the selective requirement of the AT1A receptor in leptin-mediated control of RMR. We observed that AT1A receptors colocalized with leptin receptors (LEPRs) in the ARC. Cellular coexpression of AT1A and LEPR was almost exclusive to the ARC and occurred primarily within neurons expressing agouti-related peptide (AgRP). Mice lacking the AT1A receptor specifically in LEPR-expressing cells failed to show an increase in RMR in response to a high-fat diet and deoxycorticosterone acetate–salt (DOCA-salt) treatments, but BP control remained intact. Accordingly, loss of RMR control was recapitulated in mice lacking AT1A in AgRP-expressing cells. We conclude that angiotensin activates divergent mechanisms to control BP and RMR and that the brain RAS functions as a major integrator for RMR control through its actions at leptin-sensitive AgRP cells of the ARC.


Cell Reports | 2016

Suppression of Resting Metabolism by the Angiotensin AT2 Receptor

Nicole K. Littlejohn; Henry L. Keen; Benjamin J. Weidemann; Kristin E. Claflin; Kevin V. Tobin; Kathleen R. Markan; Sungmi Park; Meghan C. Naber; Francoise A. Gourronc; Nicole A. Pearson; Xuebo Liu; Donald A. Morgan; Aloysius J. Klingelhutz; Matthew J. Potthoff; Kamal Rahmouni; Curt D. Sigmund; Justin L. Grobe

Activation of the brain renin-angiotensin system (RAS) stimulates energy expenditure through increasing of the resting metabolic rate (RMR), and this effect requires simultaneous suppression of the circulating and/or adipose RAS. To identify the mechanism by which the peripheral RAS opposes RMR control by the brain RAS, we examined mice with transgenic activation of the brain RAS (sRA mice). sRA mice exhibit increased RMR through increased energy flux in the inguinal adipose tissue, and this effect is attenuated by angiotensin II type 2 receptor (AT2) activation. AT2 activation in inguinal adipocytes opposes norepinephrine-induced uncoupling protein-1 (UCP1) production and aspects of cellular respiration, but not lipolysis. AT2 activation also opposes inguinal adipocyte function and differentiation responses to epidermal growth factor (EGF). These results highlight a major, multifaceted role for AT2 within inguinal adipocytes in the control of RMR. The AT2 receptor may therefore contribute to body fat distribution and adipose depot-specific effects upon cardio-metabolic health.


Scientific Reports | 2015

Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System.

Benjamin J. Weidemann; Susan Voong; Fabiola I. Morales-Santiago; Michael Z. Kahn; Jonathan Ni; Nicole K. Littlejohn; Kristin E. Claflin; Colin M.L. Burnett; Nicole A. Pearson; Michael L. Lutter; Justin L. Grobe

Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.


Current Hypertension Reports | 2018

Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin

Lisa L. Morselli; Kristin E. Claflin; Huxing Cui; Justin L. Grobe

Purpose of ReviewHere, we review the current understanding of the functional neuroanatomy of neurons expressing Agouti-related peptide (AgRP) and the angiotensin 1A receptor (AT1A) within the arcuate nucleus (ARC) in the control of energy balance.Recent FindingsThe development and maintenance of obesity involves suppression of resting metabolic rate (RMR). RMR control is integrated via AgRP and proopiomelanocortin neurons within the ARC. Their projections to other hypothalamic and extrahypothalamic nuclei contribute to RMR control, though relatively little is known about the contributions of individual projections and the neurotransmitters involved. Recent studies highlight a role for AT1A, localized to AgRP neurons, but the specific function of AT1A within these cells remains unclear.SummaryAT1A functions within AgRP neurons to control RMR, but additional work is required to clarify its role within subpopulations of AgRP neurons projecting to distinct second-order nuclei, and the molecular mediators of its signaling within these cells.


Cell Metabolism | 2016

FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

Stephanie von Holstein-Rathlou; Lucas D. BonDurant; Lila Peltekian; Meghan C. Naber; Terry C. Yin; Kristin E. Claflin; Adriana Ibarra Urizar; Andreas N. Madsen; Cecilia Ratner; Birgitte Holst; Kristian Karstoft; Aurelie Vandenbeuch; Catherine B. Anderson; Martin D. Cassell; Anthony P. Thompson; Thomas P. J. Solomon; Kamal Rahmouni; Sue C. Kinnamon; Andrew A. Pieper; Matthew P. Gillum; Matthew J. Potthoff


The FASEB Journal | 2015

Specific Control of Resting Metabolism by Angiotensin AT1A receptors in Leptin-Sensitive Cells

Kristin E. Claflin; Justin L. Grobe


Hypertension | 2015

Abstract P060: Angiotensin AT1A Receptors on Vasopressin-Expressing Cells are Dispensable for DOCA-salt Hypertension

Jeremy A. Sandgren; Danny W. Linggonegoro; Kristin E. Claflin; Nicole A. Pearson; Gary L. Pierce; Mark Santillan; Curt D. Sigmund; Justin L. Grobe


Hypertension | 2015

Abstract 010: The Role of Angiotensin AT1A Receptors in Leptin-sensitive Cells in Resting Metabolic Rate Control

Kristin E. Claflin; Justin L. Grobe

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Colin M.L. Burnett

Roy J. and Lucille A. Carver College of Medicine

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Matthew J. Potthoff

Roy J. and Lucille A. Carver College of Medicine

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