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Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity. Hypertension 2020 08;76(2):589-597

Date

06/09/2020

Pubmed ID

32507042

Pubmed Central ID

PMC7347451

DOI

10.1161/HYPERTENSIONAHA.120.15137

Scopus ID

2-s2.0-85087901067   12 Citations

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 (Agrp) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp 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 Agrp neuron biology, possibly secondary to altered CREB signaling.

Author List

Deng G, Morselli LL, Wagner VA, Balapattabi K, Sapouckey SA, Knudtson KL, Rahmouni K, Cui H, Sigmund CD, Kwitek AE, Grobe JL

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin
Lisa Morselli MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adiposity
Agouti-Related Protein
Animals
Arcuate Nucleus of Hypothalamus
Cyclic AMP Response Element-Binding Protein
Diet, High-Fat
Leptin
Male
Mice
Neurons
Obesity
Phosphorylation
Sequence Analysis, RNA
Signal Transduction