# Defining the pathways of cardiometabolic health after weight loss

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $744,286

## Abstract

PROJECT SUMMARY
Cardiovascular disease (CVD) and Type 2 diabetes (T2D) are leading causes of morbidity and mortality
impacting individuals across all ethnic groups in the US. CVD and T2D are largely driven by the rising prevalence
of obesity, but also impacted by genetics and environmental exposures. Weight loss surgery (WLS) is a safe
effective treatment that can sustainably reduce CVD risk and T2D incidence, but the underlying mechanisms are
not well understood. Sleeve gastrectomy is currently more popular WLS procedure, but growing evidence shows
that sustained improvement of higher magnitude is achieved with Roux-en-Y gastric bypass (RYGB). Hence,
RYGB is a useful model to study biomarkers and/or pathways of metabolic risk improvement in a high-risk
population. Although surgical changes are made to the gut anatomy, the body weight “set point” is lowered, long-
term weight and cardiometabolic disease risk are reduced, albeit with a range of success among individuals.
Human and animal studies have shown that changes in hormones, bile acids, diet, gut tissue expression and
the microbiome are conveyed to metabolically relevant organs and can provide clues on the pathways of
improved cardiometabolic health post-WLS. Because no single critical change has been identified so far, it is
possible that multiple parallel pathways convey the signals via the circulation. Metabolites are small molecules
determined by the integration of genomic, epigenetic, transcriptomic, and proteomic variation, while being
responsive to environmental factors such as diet, gut microbiota, xenobiotics, and other exposures. Metabolites
such as branched-chain amino acids, monounsaturated fatty acids, and phosphatidylcholines are known markers
of increased CVD risk and T2D, but markers of risk reduction are not yet well characterized. For Aim 1 of the
proposed project, we will identify the markers associated with CVD risk reduction and T2D resolution in a large
cohort (~1000) of individuals with RYGB from the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study
1 year after RYGB. Integrated analysis of differentially expressed metabolites and genes from human gut
transcriptome before and after RYGB will identify gut specific changes. For Aim 2, we will assess the markers
of sustained CVD and T2D risk reduction at 1 and 5 years after surgery and validate them in subjects with
metabolite data before and after medical or surgical weight loss. For Aim 3, we will identify the causal role of
known and newly identified metabolites and/or associated pathways with cardiometabolic health by mendelian
randomization. This unprecedented integration of genetics, metabolomics, transcriptomics, and clinical data in
WLS will lead to identification of biomarkers, pathways and causal links that may help devise novel non-surgical
methods to improve cardiometabolic health or preventive strategies with broad public health implications.

## Key facts

- **NIH application ID:** 10803759
- **Project number:** 1R01DK136134-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Vidhu V. Thaker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $744,286
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803759

## Citation

> US National Institutes of Health, RePORTER application 10803759, Defining the pathways of cardiometabolic health after weight loss (1R01DK136134-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10803759. Licensed CC0.

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