Mice given metabolite succinate found to lose weight by turning up the heat

July 19, 2018 by Bob Yirka, Medical Xpress report
Credit: CC0 Public Domain

A team of researchers with members from institutions across the U.S. and Canada has found that giving the metabolite succinate to mice fed a high-fat diet prevented obesity. In their paper published in the journal Nature, the group explains how they came to study the metabolite and why it helped prevent obesity in mice. Sheng Hui and Joshua Rabinowitz with Princeton University offer a News & Views piece on the work done by the team in the same journal issue. They also discuss the possibility of giving the metabolite to humans as a possible treatment for obesity.

As the researchers note, people and other mammals gain weight when they consume energy sources at a faster rate than they burn them. That energy is stored in white fat. But, as they also note, humans and other mammals also have another type of fat—brown fat—which, instead of storing energy, actually burns fuel sources and expends heat in the process. Burning such fuel, they further note, rather than storing it, prevents weight gain. Prior research has shown that the body alerts brown fat to burn fuel when it gets cold, in the form of shivering. But the mechanism by which this occurs has been a mystery. In this new effort, the researchers have identified the mechanism, and in so doing may have found a way to combat obesity.

Noting that brown fat starts burning more fuel when muscles start to shiver, the researchers looked for changes in brown fat cells when it happens. In so doing, they discovered an increase in the succinate. They discovered that as the body gets cold, muscles shiver and their cells release succinate into the bloodstream. The absorb the succinate causing them to burn more fuel, producing heat.

The researchers added succinate to water given to test fed on a and monitored them for a period of time. They report that mice given the metabolite did not become obese as happened with control mice. The researchers suggest their findings indicate that succinate might be useful for helping to combat in humans. They note that humans have less brown fat than mice, which suggests less of an impact.

Explore further: Researchers report protein kinase as the switch controlling obesity and diabetes

More information: Evanna L. Mills et al. Accumulation of succinate controls activation of adipose tissue thermogenesis, Nature (2018). DOI: 10.1038/s41586-018-0353-2

Abstract
Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease1. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP–protein kinase A signalling; this pathway has been subject to longstanding clinical investigation2,3,4. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule.

Related Stories

Researchers report protein kinase as the switch controlling obesity and diabetes

July 18, 2018
One of the research lines targeting the worldwide obesity epidemic is the manipulation of brown adipose tissue, a 'good' type of fat that burns lipids to maintain an appropriate body temperature. Researchers at the Centro ...

Researchers find way to convert bad body fat into good fat

September 19, 2017
There's good fat and bad fat in our bodies. The good fat helps burn calories, while the bad fat hoards calories, contributing to weight gain and obesity. Now, new research at Washington University School of Medicine in St. ...

Molecule that gives energy-burning brown fat its identity could lead to drugs for obesity

March 13, 2018
While most fat cells in the human body store energy, everyone has a small subset of brown fat cells that do the opposite—burn energy and generate heat. Now, Salk researchers have discovered how the molecule ERRγ gives ...

Can 'brown fat' really help with weight loss?

November 10, 2017
There have been hyped reports of late about "brown fat". Different from the fat we mostly have (white fat), brown fat is capable of burning more energy. So the theory goes: if we have more brown fat, we can lose weight. But ...

Turning on blood flow turns on fat-burning brown fat in mice

March 2, 2016
Increasing the blood flow in brown fat causes it to burn more calories in mice and may help treat obesity, a new study in the Journal of Applied Physiology reports.

Researchers rethink how 'beige' fat cells burn calories

November 13, 2017
It has been known for decades that low temperatures can trigger specialized fat cells to burn energy to produce heat, but in a new study, UC San Francisco researchers have discovered a new heat-producing pathway in fat cells ...

Recommended for you

Genetic changes associated with physical activity reported

December 10, 2018
Time spent sitting, sleeping and moving is determined in part by our genes, University of Oxford researchers have shown. In one of the most detailed projects of its kind, the scientists studied the activity of 91,105 UK Biobank ...

Study may offer doctors a more effective way to treat neuroblastoma

December 7, 2018
A very large team of researchers, mostly from multiple institutions across Germany, has found what might be a better way to treat patients with neuroblastoma, a type of cancer. In their paper published in the journal Science, ...

Progress made in transplanting pig hearts into baboons

December 6, 2018
A large team of researchers from several institutions in Germany, Sweden, Switzerland and the U.S. has transplanted pig hearts into baboons and kept them alive for an extended period of time. In their paper published in the ...

'Chemo brain' caused by malfunction in three types of brain cells, study finds

December 6, 2018
More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists ...

Hybrid prevalence estimation: Method to improve intervention coverage estimations

December 6, 2018
LSTM's Professor Joseph Valadez is senior author on a new study published today in the Proceedings of the National Academy of Sciences, which outlines proposals for a more accurate estimator of health data.

World's smallest wearable device warns of UV exposure, enables precision phototherapy

December 5, 2018
The world's smallest wearable, battery-free device has been developed by Northwestern Medicine and Northwestern's McCormick School of Engineering scientists to measure exposure to light across multiple wavelengths, from the ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

barakn
3 / 5 (2) Jul 19, 2018
Before you all rush off to the store, consider:
•NAD+, citrate, and succinate are a novel class of metabolites with inflammatory signaling capacity.
•Succinate is elevated in inflammation and sustains IL-1β production through HIF-1α stabilization.
•Succinate activates immune cells via its receptor SUCNR1 and exacerbates disease.

https://www.cell....)00221-3

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.