When people get cold, they shiver. Skeletal muscles use energy to make small jerky movements that warm up the body. Newborn babies can’t shiver, but they do have a built-in heater: globs of brown fat stored behind their shoulders.
There are two main types of fat cells, or adipocytes: lipid-storing white adipocytes and metabolically active, heat-producing brown adipocytes. People lose brown fat as they age, leaving them with mostly white adipocytes. But brown fat helps adults with type II diabetes and obesity just as much it does cold newborns. Obese mice with glucose intolerance akin to that seen in diabetes regain glucose tolerance and lose weight when given brown fat implants.
Implanting brown fat into humans is trickier though. Because adults don’t have many brown adipocytes, it’s difficult to isolate enough to use therapeutically. But the authors of a new study found a loophole.. They used CRISPR to knock out nuclear receptor interacting protein 1 (NRIP1), a gene that prevents white adipocytes from acting like brown ones (1), allowing white fat cells to act more like their brown cousins. When the researchers implanted the brown-like white adipocytes into mice fed a high fat diet, the mice became more glucose tolerant than mice implanted with unmodified white adipocytes.
While this is an interesting first step, diabetes researchers Philip Scherer from the University of Texas Southwestern Medical Center and Daniel Drucker from the Lunenfeld-Tanenbaum Research Institute, who were not involved in the study, warned that it’s a long way from the clinic.
“Translation is hard. It’s very easy to help animals; it’s much more difficult to help humans,” said Drucker. “It was a very nice study and very imaginative. I give it full marks for an animal study. And who knows, in 10 or 15 years, we might be using gene editing to fix a large number of disorders that today might be beyond reach.”
Silvia Corvera and Michael Czech, both diabetes researchers from UMass Chan Medical School, and coauthors of the study, argue that the way they edited the cells makes the therapy more translatable. Rather than exposing the cells to a lentivirus carrying a plasmid encoding Cas9 and the guide RNA (gRNA) that will lead the enzyme to NRIP1, they added the protein and gRNA directly.
“This technique reduces, at least in theory, the off-target effects of CRISPR because the fact that the Cas9 protein gets degraded within about 48 hours or so means it’s not still in the cell for days and days or weeks or months, and certainly not when we implant the cells back into the mouse. By that time, the Cas9 and the sgRNA are long gone,” said Czech.
The process is quick too. Corvera said that they could return personalized brown-like adipocytes back to a patient within a month of the first time they stepped in the clinic. First, the researchers would extract and culture white adipocytes from a biopsy of the patient’s fat, which takes about three weeks. Then they need a week to knock out NRIP1 and convert the white adipocytes to brown-like adipocytes.
“It's important to think about this in terms of the costs involved and the time because diabetes is a very common disease. In the long run, we're thinking off-the-shelf cells would be what one would need. In other words, we would want to be able to [use a patient’s own cells]. But in addition to that, we’d want to be able to also modify the cells from an individual so that they could be implanted into a different individual,” said Czech.
Scherer still sees a long road ahead for the researchers. “There's a high hurdle before this could be done more systematically at the clinical level, but on the other hand, things are moving quite rapidly in that area. CRISPR/Cas9 technology is being used already to correct specific mutations in some settings. So, it does look like this is going to be the future. And the next step for somebody like them now would actually be to provide proof of principle. Maybe not so much in the clinical setting, but perhaps in a in a nonhuman primate setting,” he said.
Czech and Corvera agree that their brown-like adipocytes aren’t ready for a human clinical trial just yet. They are gearing up to test their CRISPR technique in nonhuman primates next. They hope to answer some more questions about the brown adipocyte cells themselves and how they could be used more broadly as a therapeutic.
“It's also very important that we continue to try and understand what these cells are and what they are doing when we put them in the mice and in the monkeys. What exactly are they secreting? And how or why are they so potent systemically? We really don't know,” said Corvera.
Reference
- Tsagkaraki, E. et al. CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease. Nat Commun 12, 6931 (2021).
