Obesity Genetics: New Insights Might Mean New Therapies

Pam Harrison

August 19, 2015

A mechanism underlying the regulation of thermogenesis that is pivotal to weight gain and loss has been elucidated by a team of researchers, opening the door to novel treatments that could target the genetic underpinnings of obesity, new research suggests.

The study was published online August 19 in the New England Journal of Medicine.

"We dissected the mechanism underlying the strongest genetic association with obesity," senior author Manolis Kellis, PhD, professor of computer science and member of the Massachusetts Institute of Technology's Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts, told Medscape Medical News.

"And we found that instead of appetite or exercise, as the dogma has long prevailed, the FTO region flips a master switch that determines whether fat cells will store fat or burn it away as heat."

"The implications of this are tremendous for future therapeutics, which could bring a cure for obesity within our lifetime," according to Dr Kellis.

Under lead author Melina Claussnitzer, PhD, from Beth Israel Deaconess Medical Center, Boston, Massachusetts, investigators obtained human adipose-derived progenitor cell cultures from subcutaneous adipose tissue of 100 healthy Europeans between 20 to 50 years of age with a body mass index (BMI) in the normal range.

Fifty-two participants out of this sample carried variants of the FTO risk-allele region for obesity.

The remaining 48 participants did not carry any of the variants of the risk allele region for obesity and were referred to as non–risk-allele carriers.

Investigators then applied techniques of epigenomics, comparative genomics, human genetics, and genome editing and directed perturbations in samples from patients and from mice to dissect the regulatory circuitry and mechanistic basis of the FTO obesity-associated locus.

"Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner," Dr Claussnitzer and colleagues report.

By repressing mitochondrial thermogenesis, carriers of the FTO risk allele are more likely to store fat rather than dissipate it as heat.

As Dr Kellis emphasized, the FTO gene itself is not related to the mechanism that researchers have now elucidated that gives rise to fat storage; it is a more like a control switch that is inside that region.

Furthermore, the same research team predicted that a single-nucleotide variant was responsible for dysregulation of the target genes.

They subsequently showed that risk-allele carriers had a single nucleotide substitution where thymine was replaced by cytosine. This single genetic alteration was found to disrupt normal repression of the control region in adipocyte progenitor cells and turn on two genes, IRX3 and IRX5.

IRX3 and IRX5 act as master controllers of thermogenesis, where adipocytes dissipate energy instead of storing it as fat, as Dr Claussnitzer observed.

The enhanced expression of IRX3 and IRX5 resulting from this single nucleotide alteration promoted a shift from energy-dissipating beige adipocytes to energy-storing white adipocytes and a subsequent reduction in mitochondrial thermogenesis by a factor of 5.

By switching cytosine back to thymine, researchers found that they could turn off both IRX3 and IRX5 in risk-allele carriers and in so doing, increase thermogenesis by a factor of 7—essentially restoring levels to those of non–risk-allele carriers.

"What we found is that you can actually flip white adipocytes into beige adipocytes simply by controlling this genetic circuit we have uncovered," Dr Kellis elaborated.

"So these genetic variants flip the switch that is at the root of whether adipocyte precursor cells will differentiate into a white fat cell or a beige fat cell," he added.

"And what's really great about beige fat cells is they sit in white fat stores so they can burn away a lot more energy than if they were simply constrained in their own compartment."

Reverse Obesity Phenotypes

In fact, researchers showed that when they manipulated the new pathway in a variety of ways, they could reverse obesity phenotypes in both mice and human cells.

For example, repression of Irx3 in mouse adipocytes led to dramatic changes in energy balance, resulting in a reduction in body weight and in all major fat stores and resistance to weight gain in mice when fed a high-fat diet.

They also found that manipulation of both Irx3 and Irx5 led to an energy-balance difference in three mouse cellular models and that in each case, "our results indicated that Irx3 and Irx5 induced adipocyte lipid accumulation and repressed thermogenesis in a cell-autonomous way."

And in adipose cells taken from either risk- or nonrisk-allele carriers, knockdown or overexpression of the same target genes had a significant effect on obesity phenotypes.

"By manipulating this new pathway, we could switch between energy storage and energy dissipation programs at both the cellular and organism level, providing new hope for a cure against obesity," Dr Kellis said in a statement.

Strongest Genetic Signal

In an accompanying editorial, Clifford Rosen, MD, from the Maine Medical Center Research Institute, Scarborough, and Julie Ingelfinger, MD, from Massachusetts General Hospital Cancer Center, Boston, confirm that the FTO locus has the strongest genetic signal for BMI based on genomewide association studies, but the causal nucleotide sequence and its function have been elusive until now.

"Claussnitzer and colleagues used a range of genomic techniques, including single-nucleotide gene editing of human adipocytes, to identify an FTO causal variant, its upstream regulator, and its downstream target genes," they write.

"And their findings...provide a putative mechanism whereby polymorphic differences in noncoding nucleotide sequences change the basic function of human adipocytes from substrate storage to fuel utilization through enhanced thermogenesis."

The editorialists also note that it has been previously hypothesized that obese individuals have fewer beige adipocytes and are therefore primed to gain weight on high-fat diets.

Researchers in fact did show that variants in FTO do influence the thermogenic capacity of beige cells, resulting in phenotypic differences in BMI.

"Shifting adipocytes from energy storage to energy expenditure with pharmacologic and nonpharmacologic measures may become more feasible as the...regulatory network becomes fully defined," Drs Rosen and Ingelfinger observe.

"The study provides a strategy for translating information from genomewide association studies and ultimately for identifying new pathways in conditions beyond obesity."

The study was funded by the German Research Center for Environmental Health among others. Drs Kellis and Claussnitzer hold a patent on therapeutic targets for treatment of obesity leveraging the ARID58-rs1241085-IRX3-IRX5 regulatory circuitry. Disclosures for the coauthors are listed on the journal website. Dr Ingelfinger is a deputy editor and Dr Rosen an associate editor at the New England Journal of Medicine.

N Engl J Med. Published online August 19, 2015. Article, Editorial


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