Quick note on MIRKO mouse

Here it is again, for the 1000th time, increased glucose disposal into adipose tissue = fat tissue growth = obesity.... ( bolded part for emphasis )

White adipose tissue (WAT) plays a critical role in the development of insulin resistance via secretion of free fatty acids (FFA) and adipocytokines. Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked increase in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased. To get insight into the potential antidiabetic role of MIRKO adiposity, we have studied insulin action in WAT during a euglycemic, hyperinsulinemic clamp, and we have characterized the morphology and biology of WAT. During the clamp, there is no alteration in the expression or activation in the insulin signaling molecules involved in glucose transport through the phosphoinositide 3-kinase/Akt and CAP/Cbl pathways in WAT from MIRKO. The 53% increase in WAT mass results from a 48% increase in adipocyte number (P < 0.05) without alteration in cell size and contemporary to a 300% increase in mRNA levels of the adipogenic transcription factor CCAAT enhancer binding protein-alpha (C/EBP-alpha) (P < 0.05). There is a 39.5% increase in serum adiponectin (P < 0.01) without modification in serum leptin, resistin, and TNF-alpha. In conclusion, the MIRKO mouse displays muscle insulin resistance, visceral obesity, and dyslipidemia but does not develop hyperinsulinemia or diabetes. There is an accelerated differentiation of small insulin sensitive adipocytes, an increased secretion of the insulin sensitizer adiponectin, and maintenance of leptin sensitivity. The MIRKO mouse confirms the importance of WAT plasticity in the maintenance of whole body insulin sensitivity and represents an interesting model to search for new secreted molecules that positively alter adipose tissue biology.

and this......

During a glucose tolerance test, MIRKO mice show an increased glucose utilization in WAT, which ultimately results in increased fat mass

 Dont listen to me though, insulin doesnt make you fat, just keep counting those calories and moving more.

Guyenet solves obesity & insulin resistance connection.

Guyenet posted a paper which with 1 picture tells me everything I have thought was true is most likely true. That fat tissue growth ( adipocyte hyperplasia ) protects you from insulin resistance.

The insulin-sensitive person has clearly been able to grow new fat tissue as evidenced by the many small adipocytes you see in the picture, meanwhile the insulin-resistant person has fewer and larger adipocytes, the in-ability of fat tissue to grow is causing insulin resistance.

Why?

Because large bloated adipocytes are themselves more insulin resistant, which means less glucose uptake and less production of the lipokine palmitoleate. This lipokine released by adipocytes  is what keeps whole-body insulin sensitivity good ( glucose uptake by adipocytes is also defined as "good" insulin-sensitivity ). Dont worry if your gaining weight in the mean-time, so long as you can stay insulin sensitive so that you can keep guzzeling down loads of that cheap glucose we're selling, gotta keep our consumerism society going you know.......

I suspect the person on the left, the insulin sensitive individual, with all his nice new small adipocytes, would have a SIGNIFICANTLY harder time trying to lose weight if he did ever diet.

Oh and I just spotted this little gem in the discussion of the same paper....

It has recently been demonstrated that adipocyte number is a major determinant for fat mass in adults ( link )

This is as I said on Guyenet's other post, but I was larger ignored or challenged.

To me its clear, fat cell number determines your "body-fat" setpoint. The more fat cells you have, the fatter youll be. period.

And as I also have posted on previously, this convinces me more than ever that the only true cure for obesity is adipocyte apoptosis.

I need to cut Carbs......

Still doing 23/1 but ive stalled on the weight loss, although I have been eating a fair amount of carbs recently. Its not my fault, carb appetite goes up in the winter, exactly when you are most glucose intolerant. Other than that, it is generally just alot harder to lose weight in the winter, despite a higher metabolic rate in response to the cold, I think in general people gain weight in the winter.

Its simple, I need to cut the carbs to continue weight loss, I know it. As fantastic as 23/1 is, ( Im amazed I havent actually gained weight from the carbs ive been eating ), there comes a point where you just gotta get the insulin lower.

Through meticulous observation, I have come to see how my body reacts to certain foods. For myself, I have found that food generally falls into 4 distinct categories when it comes to weight control.....

1 ) Foods that actively promote weight loss - vinegar, coconut oil, whey protein, fish/omega3

2 ) Foods that "allow" weight loss to progress - meat, eggs, cheese, vegetables, cream, seafood, butter

3 ) Foods that slow weight loss and/or promote weight stability - Milk, Yogurt, nuts, fruit*** ( not banana )

4 ) Foods that actively promote weight gain - rice, potato, pasta, bread, banana, wheat, fruit juice, anything with added sucrose.

Im still puzzled by Dairy, despite it being highly insulinogenic, I havent been able to figure out why it doesnt cause weight gain in the same way that starch and sugars do. Dairy may produce a strong GLP-1 response, but I have a feeling that it is something to do with increased glucose disposal into adipose tissue that promotes the weight gain. Yogurt sweetened with sucrose is fattening, but plain yogurt is not.

Another look at why LIRKO cant get fat

I have to string together a bit of a loose argument here, I may be wrong, but I want to put this post up anyway.

CarbSane smugly made this post today, although in the original paper the researchers report that the LIRKO mouse has "intact" insulin signalling in adipose tissue, im slightly suspicious of this.....

The MIRKO ( muscle insulin receptor knockout mouse ) is infact obese, here it is easy for me to speculate whats happening, a lack of glucose disposal in muscle is resulting in excess glucose disposal into adipose tissue and thus causing it to grow. A study from 1993  looked at over-expressing GLUT4 in adipocytes, which resulted in increased glucose uptake into adipose tissue.

The outcome was an obese mouse but the surprising finding was the main form of fat mass increase was adipocyte hyperplasia , and not adipocyte hypertrophy.  Scary thoughts...... Adipocyte hyperplasia ( fat tissue growth ) is caused by fat mass increasing its glucose uptake.

In 2004 Khan's research group ( who is responsible for developing the insulin-receptor knockout line of mice ) did another experiment with the LIRKO mouse where they administered the dreaded PPARγ agonist rosiglitazone to the LIRKO. 


Now here's where I get speculative.....


In the abstract, Khan reports that rosiglitazone caused an increase in adipocyte size in LIRKO mice, but a decrease in adipocyte size in normal mice.  The primary way that rosiglitazone improves glucose tolerance is by stimulating the production of new, small insulin-sensitive adipocytes, i.e. fat tissue growth. This is why in the normal mice it produced a decrease in adipocyte size,  there were born more new adipocytes, and the fat mass re-distributed over the higher number of fat cells.


But not in the LIRKO, no, rosiglitazone  just made them gain adipocyte volume, the last line of the abstract is where its at....

 but both metformin and TZDs require an operating insulin signalling system in the liver for their effects in glucose homeostasis.

Remember what we just said above, TZD's improve glucose homeostasis by making fat cells multiply, if TZD's failed to improve glucose homeostasis in the LIRKO mouse then this implies that TZD's failed to cause fat cell multiplication in LIRKO. The conclusion I am drawing is as quoted, an "intact" insulin signalling system in the liver is required for fat cell multiplication and thus the development of obesity.

So the hyperinsulinemia in LIRKO probably fails to result in obesity because for some reason the PPARγ adipogenesis pathway in adipocytes is not working.

Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.

Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.

I havent seen this study before. So hepatic IR is indeed the cause of metabolic syndrome. But we already know what causes liver insulin resistance, it is elevated ChREBP in the liver, which essentially derives from a combination of high carbohydrate consumption, and also frequent carbohydrate consumption.

EDIT:

I just had this flash up aswell..

Hepatic insulin resistance directly promotes formation of cholesterol gallstones.

From reading the abstract its our old friend FoxO1 which causes this, as in metabolic syndrome, hyper-active FoxO1 promotes gallstone formation.

What is required for obesity?

This post is something of a reply to Guyenet's latest post, whereby he ends with the line "and it certainly does not erase all previous evidence suggesting that hyperinsulinemia isn't required for obesity"

This is true, and is actually obvious.

Obesity is the accumulation of excess numbers of adipocytes, and excess adipocytes can only occur in the presence of adipocyte multiplication also called adipogenesis or simply fat tissue growth.

So whats the controller of adipogenesis?

Well, so far the research has pinpointed the transcription factor PPARγ as the "Master regulator" of adipogenesis. Without PPARγ precursor cells are incapable of expressing any known aspect of the adipocyte phenotype.

Also check out this line from this abstract.....

PPARγ is the master regulator of adipogenesis, thereby stimulating the production of small insulin-sensitive adipocytes.

That part I bolded should be sending off some alarm bells in your head now with regards to PPARγ. Theres no question, if you want to get fat, just stimulate the PPARγ transcription factor inside your adipocytes....

So the next question is, what controls PPARγ in adipocytes??????????????????????

Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes

With this line.....

In explants of human adipose tissue, PPAR-gamma protein levels were significantly increased (42 +/- 3%, P < 0.05) after 12 h of incubation with insulin

That sounds something like hyperinsulinemia to me, and if hyperinsulinemia increases PPARγ, you can bet your ass that hyperinsulinemia can make you fat. The point though is that it is the downstream affects of insulin acting on the adipocyte to stimulate PPARγ that fundamentally produces obesity. Hyperinsulinemia in and of itself will be useless in producing obesity if its not hitting adipocytes and/or stimulating PPARγ.

Its very likely the FIRKO mouse cannot get fat because it cannot stimulate PPARγ inside its adipocytes.

Insulin Therapy causes weight gain

Long-term, intermittent, insulin-induced hypoglycemia produces obesity without hyperphagia or insulin resistance: a model for weight gain with insulin therapy.

I was researching some of the older studies done by Levin BE, when I found this latest study today. Apparently, its a mystery to him why insulin causes weight gain.

Insulin treatment caused a significant increase in both body weight and fat mass, accompanied by reduced motor activity, lowered thermogenesis in response to a cold challenge

Its likely that exogenous insulin therapy could be mimicked by the body in vivo, whereby you secrete extra insulin in response to carbohydrates mainly because of hepatic insulin resistance. And as per insulin therapy,  weight gain will ensue. The researchers report that the weight gain occurred in the absence of increased food intake, I have to keep repeating stuff like this because the calories in calories out meme is tough to vaccinate.

Anyway, as I said I was looking at some of the earlier research by Levin from the 1990's and he has quite a big repertoire of studies looking at "high-fat" diets in rats. Infact Levin commonly switches between using the phrase "high-fat", "high-calorie", "calories-density", in each case the diet is the same, it is a mixture of sucrose and fat, and it is quite clear that it is the sucrose causing the problems but Levin seems hesitant to acknowledge this in the texts, never mentioning the phrase "sucrose-based" diet.

One of the things Levin noted early was that there was a genetic predisposition to becoming obese on this sucrose + fat diet, as he noted, only about 50% of the rats became obese on this diet, with the other half gaining the same weight as chow fed peers. ( This genetic variance reminds me of the phenomenon in humans  whereby some people eat endless sucrose and never get fat, while others get fat easily on sucrose )

Levin, like most of the obesity research community, has been mislead and side-tracked by the discovery of red herring, leptin, in 1994, but his earlier research focused on the ability of oral or intravenous glucose to stimulate norepinephrine release into the plasma, and critically, that this increase in norepinephrine predicted which rats had the genetic predispotion to become obese on the sucrose-fat diet.

The relationship was, more norepinephrine AUC = more weight gain.

I will make another post after ive looked at more of Levin's earlier research, but to sum it up, it has something to do with the nervous system, and the brain sensing of blood glucose levels and norepinephrine release into the plasma.

The fact that higher norepinephrine plasma is correlated with weight gain leads me to think that it is catecholamine resistance in fat cells causing the problem here. Although its easy to blame insulin for weight gain, there is actually 2 sides to this story, as catecholamine resistance in fat cells will also lead to weight gain BECAUSE a lack of catecholamine binding will increase insulin sensitivity in fat cells, without any extra insulin from the pancreas.