If it were easy to lose weight, there wouldn’t be an obesity epidemic. If it were easy to lose weight, bookstores wouldn’t have multiple shelves crammed full of books with contradictory strategies for getting rid of excess body fat. If it were easy to lose weight, pharmaceutical companies wouldn’t be raking in the bucks from sales of appetite suppressants, and people wouldn’t subject themselves to highly risky surgical procedures in order to gain some ground in the battle of the bulge. And surely, if losing weight were as simple as just eating less and moving more, we’d have had obesity nipped in the bud decades ago.

Anyone who’s tried—and failed, often repeatedly—to lose weight and keep it off knows it’s anything but easy. People are always looking for an edge…anything that can offer even a slight leg up in this most difficult of endeavors. Well, a new study finds that there may be a therapeutic target to induce the browning of white adipose tissue.

The what, of what?

The browning of white adipose tissue. What, you thought there was only one kind of adipose tissue? That fat cells were fat cells? Nope. Those were the dark ages of physiology research. Things have evolved, big time. Adipose cells come in at least three varieties: white, beige, and brown, each with its own role to play in metabolism. At the risk of oversimplifying things, white adipose tissue is lazy. It mooches. It sits around, sucks up energy, and doesn’t expend a whole lot of it: “white adipocytes make up the bulk of fatty tissue in most animals, marbling our steaks and expanding around our midsections.”

Brown adipose cells, on the other hand, are the sporty ones. The ones that burn energy: they’re “highly specialized cells that dissipate stored chemical energy in the form of heat.” They literally “burn” energy. They’re loaded with mitochondria, which partly accounts for the brown color, and through the actions of uncoupling proteins (UCPs), they create “a proton leak across the inner mitochondrial membrane, thus ‘uncoupling’ fuel oxidation from ATP synthesis.” In other words, without making as much ATP, some of the fuel they burn is “wasted” as heat. Essentially, some of the fuel is lost this way, which means that more total fuel needs to be burned in order to generate the same amount of ATP in the end. And with regard to obesity, burning more fuel means losing more weight.

Since this neat party trick happens in brown adipose tissue, but not in white, the holy grail is to figure out how to create brown adipocytes, or to convert white adipocytes into beige or brown adipocytes. That is, how to turn those lazy, ne’er-do-well white fat cells into active, hungry, fat-burning brown fat cells. This process—the browning or beiging of white adipose—holds promise as an intervention for obesity.

Researchers have found that one way to nudge white adipocytes toward the beige or brown phenotype is via inhibition of a type of histone deacetylase, histone deacetylase 11 (HDAC11). HDAC inhibitors are garnering research interest for possibilities in cancer treatment, Alzheimer’s disease, improving insulin sensitivity with implications for type 2 diabetes, and more.  

Timothy McKinsey, PhD, an author on the paper exploring the role of HDAC inhibition in the generation of brown adipocytes and the beiging of white adipocytes, said, “The findings uncovered a druggable transcriptional pathway for regulation of energy expenditure, and thus suggest novel approaches for combating the global pandemics of obesity and diabetes based on HDAC11 inhibition.”

Yes, this is a “druggable transcriptional pathway,” but being that so many drugs (NSAIDs and statins, for example) have unintended, yet harmful side effects, it would be better if there were a non­-drug method for targeting the same pathway.

Well, lo and behold, there might be!

Beta-hydroxybutyrate (BOHB), the darling of the ketogenic research world, is a natural, endogenously produced HDAC inhibitor. Why spend years and millions of dollars developing a drug when people can make their own endogenous HDAC inhibitors for free? All that’s required is a very low carbohydrate intake. BOHB is more than just a byproduct of a ketogenic diet. It’s a signaling molecule that influences a broad range of metabolic processes, and may serve as a link between diet and gene expression. Ketogenic or low-carb diets do a lot more than just help people lose weight, and the signaling properties of BOHB, which are still being elucidated, may be responsible for some the beneficial effects.   

It’s sometimes said that low carb or ketogenic diets provide a “metabolic advantage” over other types of diets. Some experts believe that the state of ketosis changes metabolism such that, if matched for total caloric intake but with drastically different macronutrient ratios, compared to people on a low-fat, high-carb diet, people on a high-fat, low-carb diet would lose more weight in a given time. This is a highly contentious and controversial issue, with battles waged in the scientific literature as well as on social media. If ketogenic diets do offer any kind of advantage—and it’s not certain they do—the browning of white adipose that may be induced by the HDAC inhibiting activity of BOHB might be responsible.  

If you’d like a general overview of the role of brown adipose tissue and how it relates to insulin, ketones, and low carb diets, this talk from Ben Bikman, PhD, a professor of pathophysiology and a biomedical scientist at Brigham Young University, is a nice way to ease into this brave new world.

By Amy Berger, MS, CNS