Is the effect replicable? Yes, fairly well, here it is in a second cohort by the same group:
While this is pretty certain, the explanation is very speculative. Note the effect kicked in slightly sooner in cohort 2, I would assume that healing was a little quicker for this cohort. Maybe the researchers got better at performing the surgery. The 12 week weights are essentially identical between cohorts.
So......... Adding extra adipocytes causes overall fat loss, as in this image from Cohort 1 featured in the last post:
I find this rather interesting, to say the least. The black squares represent mice which have had subcutaneous adipose tissue implanted around their mesentery so that a significant proportion of its venous drainage enters the portal vein and goes directly to the liver.
I've looked through the data from the paper for any suggestion as to an explanation of why the weight loss occurred. There is nothing anywhere to suggest uncoupling while the mice where in the CLAMS apparatus (though calorie restriction is a good way to suppress uncoupling acutely). Calorie malabsorption through surgical damage to the mesentery seems unlikely as similar surgery to implant visceral fat gave normal weight gain compared to control mice.
So I think the mice in the SC-VIS group simply cut their ad-lib calories. Food intake was only measured over the one day in the CLAMS apparatus so we'll never know what the overall food intake was relative to controls, but I can't see any other explanation.
Which leads to the question as to why they might have cut calories, other than the obvious: They we not as hungry as the control mice. This effect occurred with mesenteric implanted subcutaneous adipocytes, but not with implanted visceral adipocytes. So we have to ask what the difference might be between the adipocyte types.
Visceral adipocytes are more insulin sensitive than subcutaneous adipocytes. They will store fat more easily and refuse to release it until insulin drops down to absolutely basal levels. On an ad-lib high carbohydrate diet this will not happen very often. As far as the liver is concerned, the visceral fat in the mesentery and omentum is non existent for most of the time. Adding extra visceral adipocytes at this site will not change this.
Subcutaneous adipocytes are less sensitive to insulin, they will store fat at high insulin levels but release FFAs easily as insulin levels fall. Obviously, they are always smaller than visceral adipocytes and they stay that way when implanted in to the recipient mice. If they are implanted in a location from which their easily released FFAs go directly to the liver they are in a position to have a metabolic effect.
Summary of the speculation so far: Visceral fat adds nothing to the FFA level of portal vein blood unless insulin level is well below that of a mouse on ad lib standard mouse chow. Placing subcutaneous adipocytes where their venous drainage goes directly to the liver supplies supplementary FFAs directly to the liver when insulin levels are merely low rather than rock bottom.
It has been known for a very, very long time that infusing FFAs in to the portal vein suppresses appetite and that this effect requires a functional vagal nerve supply to the liver. This group of rats is receiving an oleic acid infusion (if you are going to secure a long term cannula in to the portal vein then something larger than a mouse might make the surgery slightly more practical and less challenging) in to their portal vein:
Hepatic-portal oleic acid inhibits feeding more potently than hepatic-portal caprylic acid in rats
Oleic acid infused in to the portal vein at 14mcg/min for six hours reduced food intake during the 12 hour dark period from 23g in the controls to 17g in the oleic acid group. At 14mcg/min the infusion supplies 840mcg/h and over six hours this supplies just over 5mg, ie 0.005g in total dose, roughly 0.05kcal, 0.21kJ of oleic acid. This is enough to drop food intake by six grams of food at 12.4kJ/g, ie 74kJ.
This group looked at 14mcg/min because they knew it would work. We don't know how low an infusion rate could go while still having an effect on appetite (from this paper anyway). The two unanswerable questions we are left with are: What was the augmentation of FFA supply to the liver from SC adipocytes in the mesentery of the operated rats in Kahn's study? Was this enough to limit food intake? We don't know the answers but you can imagine what my guess is.
Getting access to the portal vein to either measure or infuse anything is a complete surgical nightmare. Kahn's group looked at all sorts of systemic messengers in terms of cytokines and adipokines and found absolutely nothing to explain their phenomenon.
Perhaps they were looking in the wrong place.
Peter
I guess the third question is why the SC adipocyte recipient mice actually ate a little more than the controls in the CLAMS apparatus (as judged by RQ). I'd still bet on differences in total fat mass available over-riding the stress induced refusal to eat, irrespective of degree of hunger in any mouse through the rest of the study... You could throw in cortisol, adrenalin and the lack of neural innervation of transplanted adipoctes but let's leave it simple (and possibly incorrect).
More supplementary speculation: Is the normal profound fall in appetite on induction of ketogenic eating in humans directly related to the sudden access to visceral abdominal fat, secondary to the major reduction in circulating insulin? This would suggest that the satiating effect of ketogenic diets might be more marked in people with significant visceral obesity. It would become less obvious as weight loss progresses until the majority of remaining fat is where it should be, in the non-visceral adipocytes of a normal shaped human being... The effect might even be virtually non existent in young, fit, healthy folks who would simply eat under ketosis to maintain their current rather normal bodyweight.
