Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity

Guorui Deng; Lisa L Morselli; Valerie A Wagner; Kirthikaa Balapattabi; Sarah A Sapouckey; Kevin L Knudtson; Kamal Rahmouni; Huxing Cui; Curt D Sigmund; Anne E Kwitek; Justin L Grobe

doi:10.1161/HYPERTENSIONAHA.120.15137

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Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity

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Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity

Guorui Deng, Lisa L Morselli, Valerie A Wagner, Kirthikaa Balapattabi, Sarah A Sapouckey, Kevin L Knudtson, Kamal Rahmouni, Huxing Cui, Curt D Sigmund, Anne E Kwitek, …

Hypertension (Dallas, Tex. 1979), Vol.76(2), pp.589-597

08/2020

DOI: 10.1161/HYPERTENSIONAHA.120.15137

PMCID: PMC7347451

PMID: 32507042

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Abstract

Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide ( ) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in neuron biology, possibly secondary to altered CREB signaling.

Phosphorylation

Arcuate Nucleus of Hypothalamus - metabolism

Diet, High-Fat - adverse effects

Male

Agouti-Related Protein - metabolism

Obesity - genetics

Obesity - metabolism

Animals

Leptin - blood

Sequence Analysis, RNA

Agouti-Related Protein - genetics

Cyclic AMP Response Element-Binding Protein - metabolism

Obesity - etiology

Signal Transduction - physiology

Adiposity - physiology

Mice

Neurons - metabolism

Details

Title: Subtitle: Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity
Creators: Guorui Deng - From the Department of Neuroscience and Pharmacology (G.D., S.A.S., K.R., H.C.), University of Iowa
Lisa L Morselli - Division of Endocrinology, Department of Internal Medicine (L.L.M.), University of Iowa
Valerie A Wagner - Department of Physiology (V.A.W., K.B., C.D.S., A.E.K., J.L.G.), Medical College of Wisconsin, Milwaukee
Kirthikaa Balapattabi - Department of Physiology (V.A.W., K.B., C.D.S., A.E.K., J.L.G.), Medical College of Wisconsin, Milwaukee
Sarah A Sapouckey - From the Department of Neuroscience and Pharmacology (G.D., S.A.S., K.R., H.C.), University of Iowa
Kevin L Knudtson - Iowa Institute for Human Genetics (K.L.K.), University of Iowa
Kamal Rahmouni - Iowa Neuroscience Institute (K.R., H.C.), University of Iowa
Huxing Cui - Iowa Neuroscience Institute (K.R., H.C.), University of Iowa
Curt D Sigmund - Cardiovascular Center (C.D.S., A.E.K., J.L.G.), Medical College of Wisconsin, Milwaukee
Anne E Kwitek - Department of Medicine (A.E.K.), Medical College of Wisconsin, Milwaukee
Justin L Grobe - Comprehensive Rodent Metabolic Phenotyping Core (J.L.G.), Medical College of Wisconsin, Milwaukee
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.76(2), pp.589-597
DOI: 10.1161/HYPERTENSIONAHA.120.15137
PMID: 32507042
PMCID: PMC7347451
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Publisher: United States
Grant note: T32 GM008629 / NIGMS NIH HHS UL1 TR001436 / NCATS NIH HHS T32 HL007638 / NHLBI NIH HHS R35 HL144807 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS R01 HL127673 / NHLBI NIH HHS R01 HL134850 / NHLBI NIH HHS I01 BX004249 / BLRD VA
Language: English
Date published: 08/2020
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; UI Research Foundation; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984070809102771

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