Big Boned Fat

Aug 21st, 2007 | By | Category: Medicine

See if this makes sense to you:

Weight is an intrinsic trait, determined mostly by our genes. Yet, globally the number of obese people has nearly doubled since 1980–faster than alleles can redistribute in the population.

The amount we eat is strictly controlled by regulatory systems. Each of us is endowed with an energy set-point; forced overeating makes people feel ill, until their weight drops back down. Unless, of course you are obese, where the setpoint is somehow reset to much higher than it should be; eating fewer calories to dip below the new setpoint results in a starvation response from the body, even for people who are massively overweight.

The more overweight you are, the higher your risk for heart attacks, strokes, diabetes, sleep apnea, high blood pressure and even some cancers. Unless you are active and obese; for at least some of these maladies, you’d statistically have a similar risk to sedentary skinny folk.

Confused yet? Mix in all the high emotions that come from questioning who or what is responsible for our increasingly zaftig culture, and it’s a real mess.

So, let’s add one more piece: Your bone and fat cells are talking to one another.

We’ve known for a while that being obese protects you from osteoporosis. A protein made by fat cells called leptin–also essential for regulating feeling full when you’ve had enough to eat–stimulates the bone making osteoblast cells.

The authors of a recent Cell study figured that if fat cells can stimulate bone-producing cells, the bone cells should signal back to the fat, creating a tidy negative feedback loop, where the fat cells stimulate bone producing cells (“We need stronger bones to carry around all this fat!”), and the bone cells inhibit fat formation (“Too. Much. To. Carry. Stop making fat!”)

So, what could be this signal? Bone producing cells create only a handful of distinct proteins, one of which deemed Osteocalcin. Mice lacking the Osteocalcin gene have fat bellies. Very interesting.

In this most recent study, the scientists followed this trail, and found that mice without Osteocalcin are not only fat, but are also glucose intolerant — just like people with type-II diabetes. So, less Osteocalcin, more diabetes-like symptoms.
Don’t take my word for it, here is are some snippets from figure 5 of the paper.

Oct Fatter

The mice lacking Ostocalcin (in blue) have bigger abdominal fat pads than normal mice (gray).

Oct Insulin Insensitive

Compared to normal friends, the Osteocalcin-lacking mice drop their blood sugar much less after being injected with insulin.

Oct Glucose intolerant

And Osteocalcin-lacking mice do a much poorer job of cleaning up after sugar is injected into them.

Ok, great. But how are the bone cells figuring out how much Osteocalcin to release? The scientists went on to knock out a signal receptor only in bone forming cells, Esp. Mice without the Esp receptor have more insulin producing cells (left is normal, right is from a mouse lacking Esp),

Esp KO bigger islets

more insulin production (gray normal mouse as compared to green or red mice lacking Esp),


and increased sensitivity to insulin (gray normal mouse as compared to green or red mice lacking Esp)

Esp KO insulin sensitivity

— the anti-diabetes.

So, maybe signaling through the Esp receptor blocks Osteocalcin release; remove Esp and you’d get a flood of anti-fat Osteocalcin, right? The authors tested this idea by also getting rid of only one copy of the Osteocalcin gene in mice already without Esp.

Esp and Osteocalcin double KO

It worked. Mice lacking both were more or less normal. (Holy double negatives, batman.)

So, who knows. Now for some wild speculation: Perhaps stimulating your skeleton is key in preventing diabetes. Certainly bone producing cells in mice can pump out a powerful signal that blocks belly fat, and keeps the blood sugar regulating system humming along. Next time you think about spending the whole weekend on the couch, think about the conversation between your bone and fat cells. Next time you think about spending the whole weekend on the couch, think about the conversation between your bone and fat cells.