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Trimming the fat with small proteins: Micropeptides in adipogenesis

Award Number: F32DK132927
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Trimming the fat with small proteins: Micropeptides in adipogenesis - Project Summary/Abstract Obesity is an ongoing epidemic, with more than two-thirds of adults in the US considered to be overweight or obese. Treatment options for these patients, including all FDA approved anti-obesity drugs, are ineffective for long term weight loss. The lack of effective treatments for obesity signals a gap in knowledge. The white adipose tissue is responsible for maintaining energy storage and release to maintain fuel homeostasis in the body. Disruption of white adipocyte function due to excess energy intake is a major contributor to the pathogenesis of obesity, resulting in insulin resistance, type 2 diabetes, and other metabolic diseases. Recent advancements in gene sequencing and mass spectrometry technology have allowed scientists to identify small Open Reading Frames (smORFs), which encodes functional microproteins that have a wide range of biological roles. The Saghatelian laboratory has pioneered a suite of multi-omic platforms that integrate proteomics, ribosome profiling (Ribo-Seq), and RNA sequencing to accurately annotate smORFs of less than 150 codons. By performing Ribo- Seq on models of murine adipocytes, the applicant has identified 1721 novel smORFs in the mouse genome. The great majority of these smORFs are uncharacterized. This major goal in this proposal is to address this knowledge gap by characterizing novel adipocyte smORFs that are involved in adipogenesis (Aim 1) and insulin signaling (Aim 2). Using a CRISPR/Cas9 library screen specifically targeting the 1721 novel smORFs, the applicant has already identified ~20 smORFs that specifically inhibit adipogenesis. Subaim 1.1 will validate these findings through generation of smORF knockout 3T3-L1 preadipocytes to assess how specific smORFs affect adipocyte differentiation, followed by rescue experiments through overexpressing smORFs in knockout cells. In Subaim 1.2, the applicant will dive deep into the function of a specific microprotein identified in Subaim 1.1 by characterizing its cellular location and microprotein-protein interaction. In Aim 2, the applicant will exploit the genomic and physiology data from the Diversity Outbred (DO) mice to identify smORFs that correlates with physiological changes, such as body weight, blood glucose, and triglycerides. The applicant will determine whether knocking out the smORFs identified from this analysis in 3T3-L1 cells will affect insulin signaling and glucose uptake under normal conditions and in in vitro models of insulin resistance. Completion of these studies will reveal how smORF and microproteins regulate adipocyte differentiation and insulin signaling.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $81,892 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/20/2024	NON-COMPETING CONTINUATION	$76,272
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/17/2024	NON-COMPETING CONTINUATION	$5,620
														Subtotal = $81,892

Issue Date FY: 2023 ( Subtotal = $74,292 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/10/2023	NON-COMPETING CONTINUATION	$74,292
														Subtotal = $74,292

Issue Date FY: 2022 ( Subtotal = $70,082 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	7/14/2022	NEW	$1,192
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/25/2022	NEW	$0
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/25/2022	NEW	$68,890
														Subtotal = $70,082

Grand Total All Awards = $226,266

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Trimming the fat with small proteins: Micropeptides in adipogenesis

Award Number: F32DK132927

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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