Loss of CREB Coactivator CRTC1 in SF1 Cells Leads to Hyperphagia and Obesity by High-fat Diet But Not Normal Chow Diet

Author:

Matsumura Shigenobu12ORCID,Ishikawa Fuka1,Sasaki Tsutomu3ORCID,Terkelsen Mike Krogh4,Ravnskjaer Kim4,Jinno Tomoki1,Tanaka Jin1,Goto Tsuyoshi1,Inoue Kazuo1

Affiliation:

1. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Kyoto, 611-0011, Japan

2. Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Osaka, 583-8555, Japan

3. Department of Neurology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

4. Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark

Abstract

Abstract Cyclic adenosine monophosphate responsive element–binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cyclic adenosine monophosphate. Whole-body knockdown of Crtc1 causes obesity, resulting in increased food intake and reduced energy expenditure. CRTC1 is highly expressed in the brain; therefore, it might play an important role in energy metabolism via the neuronal pathway. However, the precise mechanism by which CRTC1 regulates energy metabolism remains unknown. Here, we showed that mice lacking CRTC1, specifically in steroidogenic factor-1 expressing cells (SF1 cells), were sensitive to high-fat diet (HFD)-induced obesity, exhibiting hyperphagia and increased body weight gain. The loss of CRTC1 in SF1 cells impaired glucose metabolism. Unlike whole-body CRTC1 knockout mice, SF1 cell-specific CRTC1 deletion did not affect body weight gain or food intake in normal chow feeding. Thus, CRTC1 in SF1 cells is required for normal appetite regulation in HFD-fed mice. CRTC1 is primarily expressed in the brain. Within the hypothalamus, which plays an important role for appetite regulation, SF1 cells are only found in ventromedial hypothalamus. RNA sequencing analysis of microdissected ventromedial hypothalamus samples revealed that the loss of CRTC1 significantly changed the expression levels of certain genes. Our results revealed the important protective role of CRTC1 in SF1 cells against dietary metabolic imbalance.

Funder

Takeda Life Science Foundation

JSPS KAKENHI

Danish National Research Foundation

Center for Functional Genomics and Tissue Plasticity

Publisher

The Endocrine Society

Subject

Endocrinology

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