Thursday, November 21, 2024 11/21/2024

Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance

Award Number: R01DK089044
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Leptin, GABAergic Neurons and Feedback / Feedforward Regulation of Energy Balance Neurons in the arcuate nucleus (ARC), especially AgRP and POMC neurons, play key roles in regulating energy balance. They receive feedback information on the current status of fat stores (via leptin) and “feedforward” information on future, anticipated changes in energy balance. The neural mechanisms responsible for feedback and feedforward regulation, however, are unknown. Previous studies have suggested an important role for GABAergic neurons; in the ARC in relaying feedback regulation, and in the dorsomedial hypothalamus (DMH) in relaying feedforward regulation. With regards to feedback regulation, progress has been hampered by lack of knowledge regarding “unknown” neurons that reside in the ARC. In short, we have lacked a “parts list”. Recently, using single neuron transcriptomics, we discovered many novel GABAergic neurons in the ARC, including some which express LEPRs (Campbell JN et al., Nat Neurosci, 2017). Building on these discoveries, Aims 1 and 2 will address mechanisms of feedback regulation. Aim 3 will extend our discovery that vDMH GABAergic neurons mediate feedforward regulation of AgRP neurons. Aim 1: To use single neuron transcriptomics to assess leptin’s effects on gene expression in all subtypes of ARCLepr and vDMHLepr neurons. By capturing nuclei from all LEPR-expressing neurons in the ARC and vDMH, and looking at genome-wide transcriptional responses to leptin at the single nuclei level, this Aim will identify cell type-specific transcriptional effects of leptin in all subtypes of LEPR-expressing neurons. Aim 2: To investigate the role of novel ARCGABAergic neurons in regulating energy balance. The following neurons will be studied: LEPR-expressing, GABAergic ARCTrh/Cxcl12 neurons – which express the highest level of LEPRs in the ARC, LEPR-expressing, GABAergic ARCTbx19 neurons – which are transcriptionally similar to the leptin-regulated “RIP-Cre” neurons that control energy expenditure, GABAergic ARCTrh-Lef1 neurons – which are enriched for transcripts corresponding to human body mass index (BMI) GWAS-linked loci, GABAergic ARCSST neurons – which are transcriptionally similar to AgRP neurons and thus likely to share functions, and finally GABAergic ARCHtr3b neurons – which are transcriptionally distinct but express the interesting, unique ionotropic serotonin receptor, 5-HT3AB. Aim 3: To determine the means by which food-cue, “feedforward” regulation reaches the vDMHLepr- GABAergic à AgRP circuit. We and others unexpectedly found that AgRP neurons, in addition to being regulated by feedback signals such as leptin, are also regulated rapidly by sensory cues that “anticipate” food consumption. Importantly, this is mediated, at least in part, by vDMHLepr-GABAergic neurons which synapse onto AgRP neurons. This Aim seeks the source of this regulation. Our studies suggest a key role for a functionally distinct subset of glutamatergic neurons in the lateral hypothalamus.


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: 2025 ( Subtotal = -$6,672 )
2025	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	11/13/2024	NON-COMPETING CONTINUATION	-$6,672
														Subtotal = -$6,672

Issue Date FY: 2023 ( Subtotal = $513,189 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	4/7/2023	NON-COMPETING CONTINUATION	$513,189
														Subtotal = $513,189

Issue Date FY: 2022 ( Subtotal = $513,189 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	4/6/2022	NON-COMPETING CONTINUATION	$513,189
														Subtotal = $513,189

Issue Date FY: 2021 ( Subtotal = $513,189 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	3/31/2021	NON-COMPETING CONTINUATION	$513,189
														Subtotal = $513,189

Issue Date FY: 2020 ( Subtotal = $513,189 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/14/2020	NON-COMPETING CONTINUATION	$513,189
														Subtotal = $513,189

Issue Date FY: 2019 ( Subtotal = $533,751 )
2019	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	5/14/2019	COMPETING CONTINUATION	$533,751
2019	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	9/6/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $533,751

Issue Date FY: 2018 ( Subtotal = $400,200 )
2018	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	5/30/2018	NON-COMPETING CONTINUATION	$400,200
														Subtotal = $400,200

Issue Date FY: 2017 ( Subtotal = $400,200 )
2017	2017	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/13/2017	NON-COMPETING CONTINUATION	$400,200
														Subtotal = $400,200

Issue Date FY: 2016 ( Subtotal = $400,200 )
2016	2016	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/18/2016	NON-COMPETING CONTINUATION	$400,200
														Subtotal = $400,200

Issue Date FY: 2015 ( Subtotal = $400,200 )
2015	2015	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/3/2015	NON-COMPETING CONTINUATION	$400,200
														Subtotal = $400,200

Issue Date FY: 2014 ( Subtotal = $400,200 )
2014	2014	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/28/2014	COMPETING CONTINUATION	$400,200
														Subtotal = $400,200

Issue Date FY: 2013 ( Subtotal = $324,150 )
2013	2013	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/21/2013	NON-COMPETING CONTINUATION	$324,150
														Subtotal = $324,150

Issue Date FY: 2012 ( Subtotal = $335,907 )
2012	2012	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/21/2012	NON-COMPETING CONTINUATION	$335,907
														Subtotal = $335,907

Issue Date FY: 2011 ( Subtotal = $335,907 )
2011	2011	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/29/2011	NON-COMPETING CONTINUATION	$335,907
														Subtotal = $335,907

Issue Date FY: 2010 ( Subtotal = $434,688 )
2010	2010	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/3/2010	NEW	$434,688
														Subtotal = $434,688

Grand Total All Awards = $6,011,487

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance

Award Number: R01DK089044

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer