Feast, famine, and the genetics of obesity: you can’t have it both ways

My name is Mark Montminy and I am professor
at the Salk Institute and I am in the department of peptide biology. Up to 10% of people in
the United States, adults, have type 2 diabetes. That’s roughly 30 million individuals and
probably the biggest risk factor for developing type 2 diabetes or adult onset diabetes is
obesity. Nearly 60% of people in the United States are overweight. Not all people who
are obese develop type 2 diabetes, so it will be very useful to know which genes predispose
you to going on to becoming diabetic. Because then you can go to your doctor’s office and
he can tell you whether you are in that group that is likely to progress. The big problem
with genes that cause diabetes is that at one time we think that they had some advantage,
that they provided some advantage to people. Particularly they were talking years and years
ago, when humans survived as hunter-gatherers and there were periods of famine when, you
know, those that were able to survive by burning less fuel had an advantage over people that
burnt the food more rapidly. When we have a big meal or a series of big
meals, our body is actually remarkably able to maintain normal body weight and that’s
because of a hormone called leptin, which is made by the fat cells in our adipose, right
around the waist. And it travels in the bloodstream to the brain where it controls a part of the
brain called the hypothalamus. This control causes us to stop eating so much and at the
same time it increases the fuel-burning, it increases the ability of the body to burn
more fat, and so you stay lean. Well that works well on a short term basis but when
you’re chronically eating too much, the leptin stops working so well and eventually you become
resistant to it. It’s like becoming deaf to this signal. Our particular lab has been interested in
a group of genetic switches. The one that we’re talking about today is called CRTC 3,
and this genetic switch is actually turned on in response to certain catecholamine signals,
so let me just back up here. When leptin goes to the brain it causes the body to burn more
fuel by turning on catecholamine signaling and so by doing that it also switches on this
genetic switch CRTC 3. When it’s done for a short period of time everything works well.
We lose weight, we burn more fuel, and we stay lean. But with chronic heavy eating,
the CRTC 3 switch actually feeds back and causes the cell to shut down its response
to sympathetic or catecholamine signals and so the result is that the fat cells no longer
burn the fuel. And, as a result we gain weight. So what was so surprising about our study
is that when we removed the CRTC 3 switch from mice through a genetic trick, those mice
stay lean. Each gene in the body has two copies. If you remove both copies from the mice they
are very lean and if you remove only one of the two, then those have intermediate weight
gain compared to the ones that are what we call wild-type – they have both copies present. So that suggests that the amount of this switch
that’s in the body has a very specific effect on how much weight you can gain even under
these conditions where you would gain a lot of weight. So we wondered whether there might
be a human counterpart, could the same switch in humans contribute to the risk of obesity?
And, so we went to some collaborators at UCLA, Jerome Rotter and Mark Goodarzi who study
diabetes and obesity genes in human populations. And what they found was that there was a specific
mutation in the CRTC 3 gene that actually increases its activity and is correlated with
increased risk of obesity in Mexican-American individuals. It’s known for reasons, for a
number of reasons that Mexican-American populations have a higher risk of developing obesity and
diabetes. And so it was natural to see that some of these genes might have greater activity
in that setting. What’s surprising is that if you take the mutations that increase CRTC
3 activity, if they have two copies of those genes they’re more obese than individuals
that have only one copy or no copy. And, so just like what we saw on mice there’s this
graded relationship between the amount of the CRTC 3 switch and the chances of gaining
weight and developing obesity. So the link between CRTC 3 and obesity suggests that it
might be a useful therapeutic target for intervention in obesity and Type 2 diabetes. And through
supporting that, CRTC 3 switch is regulated by enzymes that are often very good targets
for the development of these kinds of drugs, so there is hope at least for that kind of
intervention in the future.

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