a study on mice and weight

[crnahg_yhor]

I saw a study a couple of months ago a year ago where weighted capsules were stuck inside mice, and then the mice ate less and lost weight. When I first saw it, I thought it was neat and then forgot about it.

I am not a scientist or even a person particularly capable of critiquing/analyzing/evening reading it, but I'm going to, anyway!

Paraphrased, hopefully accurately, abstract

When people (or maybe any animal?) sit a lot, they tend to weigh more than if they stand a lot, even if they exercise a lot. Why? We think there might be a regulatory effect on body weight caused by body weight.

When we put weighted capsules in rats and mice, they ate less and they weighed less (accounting for the extra capsule weight). Leptin, a hormone that affects appetite, is primarily(?) made in fat, so extra leptin from fat is probably not the cause of this appetite reduction; so we think there is another regulatory system.

It is also the case that osteocytes, a kind of cell in bone, are affected by changes in bone strain. Mice with (without? fewer) osteocytes didn't lose weight when they had weighted capsules added, so we think that our proposed non-leptin weight regulation mechanism, the "gravitostat", depends on how much force is applied to bones.

We think that the gravitostat is likely to explain why people/animals that sit more tend to weigh more than those that stand more. We think that signals from this gravitostat is used with signals from leptin to regulate body weight such that it's bounded both above and below.

I had some questions, which I didn't really separate from my paraphrase, and I probably should've. Wow, that ✨Cornell Notes Method✨ they tried to make us use in like 6th grade would've been useful here.

results

Both the control and test groups of rats & mice got capsules implanted in them; the test groups got weights, and the control didn't. The capsules were 15% of body weight for the test and 3% for the control, but they don't say what the capsules were made out of. It's probably something sensible like silicone, ... but silicone is squishy if there's nothing in it, yeah? Maybe not on the scale of a teeny-weeny thing, though. I know titanium is used for hip replacements, but titanium is overkill here, yeah? So maybe stainless steel?

Figures A (rats) & B (mice) show that the test group weighed less on average at the end of 2 weeks than the control group; both groups initially lose body weight, probably because anesthesia sucks? It's interesting that the control rats weigh more than baseline after 2 weeks, and the mice don't. I'm not sure if it's that young rats were used and they were still growing, if rats weigh more the longer they live, if rats recover from surgery faster than mice, ...

At least in mice, at the end of two weeks, the test mice had less adipose/fat tissue than the control mice (C); they also had less leptin (E). Increased leptin depresses appetite, right? So it's neat the the test mice were eating less ?still? at the end. (Were they? F, mice, and G, rats, is days 4-6, in the first half.)

Hey! You just snuck that "we only had like 8 rats and 10 mice" in there. 8 and 10 in total, or in each group?

I was just about to ask, what happens if you give a control group the same amount of food that that test group ate? And they answered me immediately; apparently that's what pair-feeding is. (H) Otherwise-control mice fed the same amount as the test-mice lost the same amount of body weight. (n=9? 3 in each group, or 9 in each group? Are these really small numbers? These sound like really small numbers.) This means that the weighted mice are not overall expending extra energy, but are eating less.

Fig I is a little confusing, but I think what's happening: After the 2 week period, they did another surgery on the mice(? or rats? or both?), in which either the heavy capsule was replaced with a new, unweighted capsule, or a new, weighted capsule. Both groups again lost body weight (anesthesia and recovery suck?) and then the newly-unweighted group gained some, compared to where they were before the second surgery, and the re-weighted group climbed back up but not to where they were before the second surgery. It's unclear, to me, if that gain was leveling out or not, though. I also wonder that the surgery weight loss is a constant, then, because they seem to have lost a greater proportion of their bodyweight in round 2? Maybe not constant, given that in round 1, the light and heavy capsule rodents lost differing amounts of weight initially, and in round 2, they lost nearly the same initially.

J and K go on to clarify that the mice with the newly-light capsules mostly gained fat, not muscle.

L is measuring HOMA-IR, 'homeostatic model assessment', which measures insulin resistance. M is glucose; N is the integral of glucose; likewise with O and P about insulin. I don't really know what to make of it.

Q answers my 'what happens long-term?' question: they both eventually end up above baseline. Why?

So far, this study seems neat, because at least some of my "Did you try (blah)?" questions are answered before I even had them. "Did you try it on mice that were bad at leptin?" (Figure 2 A-D). Still, why did these mice keep gaining weight? Do these mice just grow, infinitely? Do you eventually get huge mice? Does it stop?

Since the body weight reducing effect of increased loading was caused by reduced food intake, we analyzed the expression of appetite regulating genes in the hypothalamus. Increased loading augmented the expression of the obesity promoting neuropeptides AgRP and NPY (Fig. S1J). These two peptides are expressed by essentially the same neurons in the arcuate nucleus of the hypothalamus and their expression is suppressed by leptin. Therefore, the increase in AgRP and NPY expression is likely to be a failed compensatory mechanism induced by low fat mass and low serum leptin in the mice exposed to increased loading (Fig. 1 D and E and Fig. S1J), consistent with a leptin-independent mechanism for increased loading to reduce body weight.

Okay, I'm having a hard time understanding this segment.

Since they lost weight because they ate less, we looked at what appetite-regulating genes were doing in the hypothalmus. There were increased concentrations of neuropeptides AgRP (Agouti-related protein/peptide) [not very much to do with the fur color Agouti] and NPY (neuropeptide Y) in mice with extra weight; AgRP and NPY are produced at the same time as each other in a certain part of the hypothalmus, and increase appetite and decrease energy expenditure, and are suppressed by leptin. We think that the increased amounts of AgRP and NPY is because of the low fat mass and low leptin amounts in the weighted mice, and [???] because this was not able to counteract the weight loss, we think this is evidence that there is a mechanism for reducing body weight other than leptin. [I'm reasonably sure I have it right up to the ???, but after that, I'm not sure.]

Osteocytes

okay diptheria what?

When you put a bunch of force on the bone suddenly and repeatedly, osteocytes make that area stronger. I think this is why, frex, running makes bones get stronger, probably, maybe. We think it's possible that the static increase in load (like increased body weight) might also cause osteocytes to Do A Thing, and we think this an important part of our proposed Gravitostat mechanism.

We tested this by using... something to do with diptheria? I'm pretty sure this isn't important for understanding the paper, but also, what the fuck. ... to deplete some mice of osteocytes. (S2, fig A/B have a picture. There sure are fewer osteocytes, and the ones there are ?smaller?. H: I know lacuna! That's hole, in latin. Empty holes per total holes.)

Anyway, even if you load up the osteocyte-depleted mice in the same way you load up the normal mice, after the initial weight loss of surgery, they regain weight in the same way that unloaded ones do. (3A shows normal mice, loaded and unloaded; 3B shows osteocyte-depleted mice, loaded and unloaded). This makes a good argument that the osteocytes are doing something important.

We know that osteocytes make osteocalcin, and that osteocalcin has something to do with metabolism, so we expected that osteocalcin (or something similar) is part of the Gravitostat mechanism. [huh! that osteocalcin does metabolism stuff seems to have been known/expected/believed since at least 10 years ago, although it's not clear to me if it was known/expected/suspected/etc what makes osteocalcin occur.] Having said that, we didn't see much change in osteocalcin levels (or the other, obvious, similar thing) in the heavy-capsule mice.

Other, obvious routes that this could work by but doesn't

There are other body weight regulating things, like ghrelin (a hormone that increases appetite, produced in the gastrointestinal system); we checked to see if the weight-capsules worked on mice that didn't have ghrelin receptors. It did. (Aside: ghrelin crosses the blood-brain barrier, so Exogenous Ghrelin can be a thing.)

Neuropetitde alpha-MSH (alpha-Melanocyte-stimulating-hormone), responsible primarily for... pigmentation of hair and skin... also has something do with with appetite and metabolism. In mice lacking receptors for it, weighted capsules still make them lose weight.

Signals that estrogen receptor-alpha receives regulate fat mass and bone mass; in mice lacking that receptor, they still lose weight when loaded.

We thought to check to see if noradrenaline or choline were doing something, but we found the normal amounts.

Discussion

We found that something that isn't leptin is probably influencing the body weight of mice and rats.

In humans, we know that signals from leptin are necessary to prevent high weights. Nonetheless, they clearly aren't sufficient, and we call that leptin resistance.

We think that this weight-loading mechanism thing is necessary to prevent high weights, as well. We think this is a useful thing to study in humans. We expect that a reason that sitting a lot is correlated with higher weights is because the osteocytes aren't loaded while people are sitting.

[Hmm, I think they were using 'gravitostat' to refer to a more specific thing that I was thinking it was. Well, whatever.]

We think there is something we are calling a 'gravitostat' that regulates fat mass, independently of leptin. It has sensors, probably in the lower, weight-bearing parts of the body, at least some of which are osteocytes. (In rats & mice, both the front arms and the back legs bear weight. What happens if you removed osteocytes from just the back or front? Can you selectively do that?) The 'integrative center' for the gravitostat is probably in the brain. The effect of the gravitostat is to reduce appetite.

We should do more studies to see if the gravitostat is why standing seems to be a good weight-loss technique. We should do more studies to see if we can directly poke or mimic the gravitostat, with drugs.

Materials

At this point i realize the abbreviation 'sc' they've been using is not latin 'scilicet' but instead probably 'subcutaneously'.

I still don't know how many mice there were!

anyway

A response to the study got published, too. I think it's approximately "That's interesting, and here are some results which support it (effects of hypergravity and microgravity on rodents), and here are some that don't support it (astronauts)."

I've been sitting down the entire time I've been writing this, and though we have a standing desk, currently there's a pile of cat toys, electronics, and blinkenlights in front of it; maybe I'm going to clean today.

Comments

Nifty if true, but . . .

[another_normal_anomaly]

Nifty if true, but the small sample sizes and the short timescales involved make me very skeptical. Two weeks is barely long enough to observe weight changes in humans in response to major changes in lifestyle, even without surgery complicating things. Mice and rats are small enough that I could believe their weight might respond to changes in other factors faster than humans, but if they barely tracked past the end of the surgery recovery period there are probably all sorts of confounders from the animal's body going "oh god I was knocked out and now there's a foreign object inside me, what do".

That said, if this is true, it suggests that wearing a weighted vest all day including while sitting at my desk (this is a thing I have recently started doing) might be useful for more than just shoulder/core strength.

Re: Nifty if true, but . . .

[crnahg_yhor]

The weighted vest is what reminded me of it!

Another thing that feels weird to me: there's a 49-day graph, and the mice in both the weightless capsule group and the weighted group, at the end, weigh more than when they started (though the weighted mice are lighter than the weightless mice). Do mice just gain weight constantly, were they not fully grown, ...?

I didn't realize until now that most mice weigh less than an ounce. Whatever the weight was, for the mice, it would've been around 2 grams, I think? and, guessing that it's stainless steel, it would have a volume of around .25ml. ... This works out to be about twice as big as like an implanon. And you can put that in a person with just local anesthesia, but... twice as big! On a mouse! So I guess I don't have any really good bounds on what surgery recovery must be like for a mouse.

Re: Nifty if true, but . . .

[another_normal_anomaly]

I'm glad I reminded you of a thing! And yeah, I think the takeaway here is "don't implant chunks of metal into yourself unless you have a good reason, and don't be surprised if doing so has consequences".