Researchers find glycolysis links to gene transcription via NAD+

May 11, 2018 by Bob Yirka, Medical Xpress report
Compartmentalized NAD+ biosynthesis by NMNATs regulates adipogenesis through PARP-1. NMNATs synthesize NAD+ from nicotinamide mononucleotide (NMN) and adenosine triphosphate. Nuclear NMNAT-1 provides NAD+ for nuclear ADP-ribosylation and gene regulation by PARP-1, whereas cytoplasmic NMNAT-2 provides NAD+ for cytosolic ADP-ribosylation and cellular metabolism. Competition between NMNAT-1 and NMNAT-2 for their common substrate, NMN, promotes compartmentalized regulation of NAD+ levels, allowing for discrete nuclear and cytoplasmic events. The fluorescent images of NAD+ in the bottom panel were generated using a NAD+ sensor localized to the nucleus (left) or the cytoplasm (right). Credit: Science (2018). DOI: 10.1126/science.aan5780

A team of researchers at the University of Texas has found NAD+ synthesis and consumption integrate glucose metabolism and adipogenic transcription during adipocyte differentiation. In their paper published in the journal Science, the group describes their research into how glucose is converted into fat in the body and what they found. Sophie Trefely and Kathryn Wellen with the University of Pennsylvania and Drexel University, respectively, offer a Perspective piece on the work done by the team in Texas in the same journal issue.

As obesity rates continue to climb around the globe, scientists continue to explore why it is happening. In addition to studying the psychological aspects involved, scientists would also like to better understand why eating too much makes people gain weight. In this new effort, the researchers looked more closely into why consuming too much glucose causes the body to produce fat.

Prior research has shown that (NAD) is an important molecule that plays a role in a wide variety of physiological and pathological processes. Its oxidized form, NAD+, has also been found to act as a cofactor in metabolic pathways, and more importantly, perhaps, is consumed by various enzymes. Once consumed, NAD+ is broken down into nicotinamides and ADP-ribose. This, the researchers note, means that NAD+ must be resynthesized for normal cellular function to continue. They further note that some prior research has suggested that lower-than-normal levels of NAD+ can alter , leading in some cases to higher disease susceptibility.

The researchers believed that and gene regulation might be connected to the synthesis of NAD+, so they embarked on a series of experiments to back up their ideas. In so doing, they discovered evidence indicating that compartmentalized (within membrane-bound organelles) NAD+ synthesis and subsequent consumption served to integrate metabolism and adipogenic transcription as part of the adipocyte differentiation process.

The study results, Trefely and Wellen note, show that metabolism involving membrane-bound organelles is distinct from that involving small molecules such as NAD+, which can pass through nuclear pores, allowing metabolic equilibrium.

Explore further: Inhibiting metabolism found to be effective in treating aggressive form of lung cancer

More information: Keun Woo Ryu et al. Metabolic regulation of transcription through compartmentalized NAD+biosynthesis, Science (2018). DOI: 10.1126/science.aan5780

Abstract
NAD+ (nicotinamide adenine dinucleotide in its oxidized state) is an essential molecule for a variety of physiological processes. It is synthesized in distinct subcellular compartments by three different synthases (NMNAT-1, -2, and -3). We found that compartmentalized NAD+ synthesis by NMNATs integrates glucose metabolism and adipogenic transcription during adipocyte differentiation. Adipogenic signaling rapidly induces cytoplasmic NMNAT-2, which competes with nuclear NMNAT-1 for the common substrate, nicotinamide mononucleotide, leading to a precipitous reduction in nuclear NAD+ levels. This inhibits the catalytic activity of poly[adenosine diphosphate (ADP)–ribose] polymerase–1 (PARP-1), a NAD+-dependent enzyme that represses adipogenic transcription by ADP-ribosylating the adipogenic transcription factor C/EBPβ. Reversal of PARP-1–mediated repression by NMNAT-2–mediated nuclear NAD+ depletion in response to adipogenic signals drives adipogenesis. Thus, compartmentalized NAD+ synthesis functions as an integrator of cellular metabolism and signal-dependent transcriptional programs.

Related Stories

Inhibiting metabolism found to be effective in treating aggressive form of lung cancer

April 12, 2018
Researchers from UCLA and Long Beach Memorial Medical Center have found that two targeted therapies could be more effective if used in combination to treat squamous cell carcinomas of the lung. The two drugs, MLN128 and CB-839, ...

New regulator of liver metabolism discovered

September 29, 2017
Researchers from Charité - Universitätsmedizin Berlin have identified an enzyme that has a major effect on glucose utilization in liver cells. The enzyme, retinol saturase, helps these cells adapt to variations in glucose ...

Potential enzyme as therapeutic target for diabetes

January 26, 2018
Abnormalities in glucose uptake by the liver (or hepatic glucose uptake; HGU) causes elevations in blood glucose levels following meals, a state that is known as postprandial hyperglycemia. Such abnormalities are observed ...

Men with impaired glucose metabolism should avoid high-carbohydrate foods in the evening

March 9, 2017
According to a nutrition study led by the German Institute of Human Nutrition (DIfE), a partner of the German Center for Diabetes Research, the so-called internal clock also influences how people with impaired glucose metabolism ...

Researchers identify new vitamin B3 pathway

August 6, 2015
Researchers at Beth Israel Deaconess Medical Center (BIDMC) have identified a new vitamin B3 pathway that regulates liver metabolism. The discovery provides an opportunity to pursue the development of novel drug therapies ...

Bright light alters metabolism

May 19, 2016
Exposure to bright light could affect your metabolism, reports a new Northwestern Medicine study.

Recommended for you

Age-related increase in estrogen may cause common men's hernia

October 16, 2018
An age-related increase in estrogen may be the culprit behind inguinal hernias, a condition common among elderly men that often requires corrective surgery, according to a Northwestern Medicine study was published Oct. 15 ...

New findings cast light on lymphatic system, key player in human health

October 16, 2018
Scientists at the Oklahoma Medical Research Foundation have broken new ground in understanding how the lymphatic system works, potentially opening the door for future therapies.

New model suggests cuffless, non-invasive blood pressure monitoring possible using pulse waves

October 16, 2018
A large team of researchers from several institutions in China and the U.S. has developed a model that suggests it should be possible to create a cuffless, non-invasive blood pressure monitor based on measuring pulse waves. ...

Discovery of inner ear function may improve diagnosis of hearing impairment

October 15, 2018
Results from a research study published in Nature Communications show how the inner ear processes speech, something that has until now been unknown. The authors of the report include researchers from Linköping University, ...

Team's study reveals hidden lives of medical biomarkers

October 12, 2018
What do medical biomarkers do on evenings and weekends, when they might be considered off the clock?

Widespread errors in 'proofreading' cause inherited blindness

October 12, 2018
Mistakes in "proofreading" the genetic code of retinal cells is the cause of a form of inherited blindness, retinitis pigmentosa (RP) caused by mutations in splicing factors.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.