Liver fat oxidation reduces appetite and bodyfat

The infusion of either caprylic acid or oleic acid into the hepatic portal vein results in liver fatty acid oxidation and a concomitant reduction in food intake ( and therefore probably also bodyweight ). (1, 2)

The same thing was also seen in a mutant mouse model, they over-express Fructose 1,6-bisphosphatase in the liver of rodents and it decreases food intake and bodyweight. ( 3 ) Infact this paper puts forward very strong support for the idea that the liver can actually directly control appetite by changing orexin proteins in the brain, NPY/AgRP.

What else can enhance liver fat oxidation? Metformin! It does this by increasing liver AMPK.

There is an ugly one for the ladies next, ovariectomized rats have decreased liver fat oxidation ( 4 ). Estrogen-deficient states are associated with hepatic steatosis. ( fatty liver ). Fatty acid oxidation rate was lowered by 34% (p<0.05), associated with 114% higher (p<0.01) hepatic triacylgylcerol content in the liver of ovariectomized as compared to intact rats. Estrogen replacement prevented all of these changes.

This is further evidence why women have problems with their weight post-meno. And another reason why CICO is complete bullshit. All the evidence seems to support the idea that CICO is an affect, not a cause. ( 5 ) Higher respiratory qutioent strongly predicts weight gain, the way that I personally think it works is like this.....

Fat oxidation -> low respiratory quotient -> reduced food intake -> reduced bodyweight. There are quite a few studies on pubmed showing that if you inhibit fat oxidation with drugs this immediately stimulates food intake in rodents.

Exendin-4 activates glucokinase

Just a small note. Exendin-4 is a GLP-1 receptor agonist. Glucokinase is an enzyme that senses glucose levels, especially in the liver, where increased glucokinase levels reduce endogenous glucose production and increases glycogen synthesis.

People suffering from diabesity secrete significantly less GLP-1 in response to an oral carbohydrate load. Diabesity sufferers also have reduced glucokinase activity in the liver. See the link? ( 1, 2)

If you have Diabesity and eat 100g of glucose, you may only secrete enough GLP-1 for your liver to see ~50g of that glucose. What happens to the rest of the glucose that your liver doesnt see?

Well, since your liver cant see it, it cant do anything about it, the glucose may hit circulation where it causes the pancreas to secrete extra insulin ( hyperinsulinemia? ) Excessive glucose floating around in your blood that your liver doesnt know about cant be any good, glycation is serious business!

Remember also that glp-1 is a satiety hormone, it makes you eat less, and it also encourages fat oxidation over carbohydrate oxidation, I cant help but wonder now if this is exactly because GLP-1 activates glucokinase. Again peter was on the money with this post. If your liver is broke, through some combination of hepatic IR and reduced glp-1 secretion, you need to put down the carbs!

If you cant activate glucokinase to the correct amount of glucose you eat, then you cant do "paleo", lmao.

CICO fails again - ( more ELMM nonsense )

Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise - a randomized controlled trial in overweight sedentary males.

CICO = calories in calories out

ELMM = eat less move more

The amount of weight loss induced by exercise is often disappointing.

Nay, its because CICO is complete bullshit.

Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate (300 kcal/day) and 22 to a high dose (600 kcal/day) exercise group for 13 weeks, corresponding to approximately 30 and 60 minutes of daily aerobic exercise, respectively.

Right ok, so we have 1 group doing moderate exercise, and 1 group doing heavy exercise, and by the masterful universal laws of calories in and calories out and thermodynamics etc etc, the higher exercise group burn more calories and thus should have lower fat mass in the end. Right??! Surely thats irrefutable?

fat mass (MOD: -4.0kg, P<0.001 and HIGH: -3.8kg, P<0.001) decreased similarly in both exercise groups.

Actually according to the above numbers , 4kg is more than 3.8kg and therefore the people performing the "least" amount of exercise lost more fat mass. DUDE WTF? ELMM CICO!

Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or non-exercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise.

The group doing more exercise did not eat more calories to compensate.

In conclusion a similar body fat loss was obtained regardless of exercise dose

Summary :-

Dont waste your time trying to lose weight by moving more than 30 minutes per day. All movement over 30 minutes per day = violates first law of thermodynamics.

What do you need to avoid diabetes?

Some pre-conceptions put forward by this paper are startling, even if you have zero insulin signalling in skeletal muscle AND adipose tissue ( i.e. no insulin receptors ) you can still be protected from diabetes provided the insulin signalling in brain, liver, and pancreas is working properly. Although your glucose tolerance is worsened, mainly because skeletal muscle is the primary site of glucose disposal in the human body ( 1 )

So to repeat that, aslong as you have functional insulin signalling in brain, liver, pancreas, you should be protected from diabetes, if you mess with insulin signalling in any of those organs, you get diabetes.

These findings are surprising as they ostensibly indicate that insulin action in tissues with insulin-dependent glucose uptake, such as muscle and fat, is dispensable for metabolic control.

This helps confirm one of my long-time held beliefs, that anaerobic exercise can really help with glucose tolerance ( because it helps with skeletal muscle insulin sensitivity ), however, it will not go anywhere towards helping diabetes if you have screwed insulin signalling somewhere in either brain/liver/pancreas.

There is also this paper from 1998 which came to the same conclusion, i.e. that disruption of insulin signalling in both skeletal muscle and adipose tissue is not sufficient to cause diabetes, although again, it does worsen glucose tolerance.

Lastly, it seems this research group have also caught onto the fact that fatty liver, i.e. NAFLD may just be an affect of insulin resistance, and not the CAUSE. This is the same conclusion that one is lead too after reading Lustigs paper on selective hepatic IR.

Obesity != Diabetes ( Strike 1 )

Some obesity researchers think that obesity is "causative" of insulin resistance and diabetes. What is obesity?

At the fundamental level, obesity is nothing more than a dramatic increase in the size of the lipid droplets in the adipocyte, see here for a diagram . ( Damn why the fuck is that study behind a paywall ? :(

Obesity is also an increase in the total number of adipocytes you have but thats another story....

But anyway, the point is this, if obesity was "causative" of diabetes and insulin resistance, then what you are essentially saying is that an increase the average size of the lipid droplets in adipocytes is straight up causative.

Is that true?

This clever study says NO!

Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance.

Overexpression of PEPCK in adipose tissue leads to increased glyceroneogenesis and thus an increase in average lipid droplet size ( i.e. obesity ), but there is no accompanying insulin resistance or T2DM.

Thats a VERY big strike for the theory that obesity is "causative" of insulin resistance and T2DM. NO baby, whats more likely is that obesity is an unfortunate side affect of the same "thing" that is promoting T2DM, i.e. a red herring, its the smoke that tells you there's possibly a fire nearby. But the smoke absolutely does not CAUSE the fire, if there is indeed a fire at all.

On Fat Balance

The role of dietary fat in adipose tissue metabolism

My latest musings on adiposity come courtesy of this paper. The authors try very hard in this paper to argue that polyunsaturated fats in the diet are "good" while saturated fats are "bad". However, if one reads past their bias, there are a few very interesting lines that caught my eye.

the rate of fat oxidation must be set largely by the gap between total energy expenditure and energy intake in the form of protein and carbohydrates, rather than by the amount of fat consumed on a given day.

This is as I was arguing before back in this post that ultimately, the rate of fat oxidation is determined by the absence of both Carbs and protein in the diet. The paper tries very hard to argue that the fate of dietary fats is almost always that of storage, but this runs counter-intuitive to the macroscopic affects observed when one consumes a diet of mostly lipid compared to mostly carb. It was known back in 1964 that a diet of mostly lipid produces greater fat loss than a diet of mostly carb.

Next, we move on to the idea that the composition of dietary fats strongly influences the composition of the lipid membrane present in fat cells. That is, a diet high saturated fats makes lipid membranes mostly saturated, and a diet high in polyunsaturated fats makes lipid membranes mostly unsaturated. The next quote was particularly interesting........

The amount of insulin bound and the translocation of GLUT4 transporter induced by this hormone increases with the content of polyunsaturated fatty acids in membrane phospholipids.

Whoa! This is big. What this is basically saying is that a diet high in polyunsaturated fats favors lipid membrane compositions that are more unsaturated and thus increases the insulin sensitivity of fat cells! Oppps! When I read this quote my brain was immediately backflashed to the video of urgelt talking about how farmers feed pigs polyunsaturated fats to "fatten" them up! There was also this very interesting post by that paleo guy about a very similar thing, i.e. feeding lots of polyunsaturated fats to animals increases obesity!

The message is clear to me, stay the fuck away from vegetable oils!

In a slightly divergent topic, I found this paper that ties together some theories of mine.

Higher fasting plasma concentrations of glucagon-like peptide 1 are associated with higher resting energy expenditure and fat oxidation rates in humans

This rather nicely ties together the ideas that a higher respiratory quotient ( i.e. high carb burning ) is positively associated with increases in fat gain, and also that a reduced incretin response to food is almost straight up causative of obesity. OK, so, glp-1 increases fat oxidation, meanwhile a high carb burning metabolism and rapid consumption of glycogen stores ( at rest ) results in hunger and fat gain.

The connection is this paper. To quote.......

Only GLP-1-(23), however, significantly increased the rate of glucose storage as glycogen

Bingo! So glp-1 increases glycogen synthesis, and probably also inhibits glycogen breakdown, under conditions of higher glp-1, glycogen stores are preserved and thus the metabolism runs on fat ( as it should! ).

Now it is slightly easier to understand why Carbohydrate balance predicts weight and fat gain in adults, My ( educated ) guess is that people with a higher carbohydrate balance have this BECAUSE their glp-1 is higher, and higher glp-1 encourages fat oxidation over carb oxidation and thus helps resist obesity.

Leptin resistance is real

Just a quick post, unfortunately Leptin is quite complicated. The main site of action for leptin is the hypothalamus. After reading this paper I was quickly lead to the discussion about SOCS3 and leptin resistance. ( SOCS3 = suppressor of cytokine signaling 3 )

From this paper we learn that SOCS3 inhibits the actions of leptin in the brain by binding to the leptin receptor there. Not good!

Next, we see from this paper that obese people have elevated levels of SOCS3, as shown in the graph below. ( grey bars = obese subjects, black bars = lean subjects )

The whole thing is further complicated by the fact that the liver secretes a protein sOb-R that binds to leptin and makes it inactive. This whole stuff was talked about by Peter back in this post. Blah it seems I am late to the party once again! I am making this post rather just to drill this stuff into my head. It seems the reason that the LIRKO mouse is not fat is because it pisses alot of glucose ( calories ) out via glycosuria and the mouse is also super sensitive to leptin via very low SOCS3.