# Mechanisms for regulation of a novel class of anti-diabetic lipids

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $760,278

## Abstract

The growing epidemic of obesity and Type 2 diabetes requires new strategies for prevention and treatment.
We discovered a structurally novel, family of endogenous bioactive lipids, branched fatty Acid esters of
Hydroxy fatty Acids (FAHFAs). A subfamily, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), has
anti-diabetic and anti-inflammatory effects. PAHSA levels are low in serum and adipose tissue of insulin-resistant
versus insulin-sensitive people, and levels correlate highly with insulin sensitivity. In insulin-resistant
mice, PAHSA administration improves glucose tolerance and insulin sensitivity, in part by enhancing insulin
action to suppress hepatic glucose production which results from improved lipolysis suppression. PAHSAs are
anti-inflammatory and reduce colitis severity and the incidence of auto-immune Type 1 diabetes in mice. We
have made tremendous strides in discovering new activities for PAHSAs, identifying additional families of
bioactive and storage forms of FAHFAs, and uncovering biochemical pathways and enzymes that control
tissue FAHFA levels. These studies underscore that FAHFAs are a highly-regulated class of lipids with
tremendous translational potential. The overall objective of this proposal is to determine the mechanisms that
regulate tissue and serum FAHFA levels in physiologic and disease states by identifying enzymes and
pathways that regulate FAHFA biosynthesis, degradation and incorporation into other lipids. We will use
innovative and robust assays we developed with isotopically-labeled FAHFAs and their precursors to measure
FAHFA synthesis and degradation in vivo, target specific pathways of FAHFA regulation, and identify
additional, missing enzymes and other factors that regulate FAHFA biosynthesis, degradation, transport and
storage. We have already made terrific progress by identifying 3 FAHFA hydrolases and the first FAHFA
biosynthetic transacylase. We will delineate this new biosynthetic pathway using novel mechanistic studies.
We also propose a highly complementary, innovative, systems analyses that will integrate transcriptomic data
with targeted FAHFA measurements. First, we will take advantage of the large, reciprocal regulation of
FAHFAs in our unique mouse models with altered expression of Glut4 and ChREBP, to find unknown factors
mediating this regulation. Since Glut4 and ChREBP expression in adipose tissue from humans correlates with
insulin sensitivity and adipose FAHFA levels, genes identified with these experiments could have clinical
relevance. The second approach exploits the natural genetic variation in the diversity outbred (DO) mice,
which have as much natural genetic variation as the human population. We will perform targeted
measurements of ~300 different FAHFA isomers in adipose tissue, liver and plasma of ~500 DO mice and
leverage the existing genetic and transcriptomic data from DO mice to find new "drivers"/regulators of tissue
FAHFA levels. These studies will advance our understa...

## Key facts

- **NIH application ID:** 10378154
- **Project number:** 5R01DK106210-07
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** BARBARA B. KAHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $760,278
- **Award type:** 5
- **Project period:** 2016-04-20 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378154

## Citation

> US National Institutes of Health, RePORTER application 10378154, Mechanisms for regulation of a novel class of anti-diabetic lipids (5R01DK106210-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10378154. Licensed CC0.

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