Mitochondria and High Fat Diets

Lots of buzz over mitochondria of late.  So I thought I'd share this find:

High-fat diets cause insulin resistance despite an increase in muscle mitochondria

It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria.    In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria.

This study used male Wistar rats, a "normal" strain not prone to diabetes, etc.  They were fed ad libitum

1. Standard chow diet (PicoLab Rodent Diet 20, 5053):  23.5% P/ 11.9% F/ 64.5%C.  (I'll use SC)
2. High-fat flax seed/olive oil diet:  20% P (casein) / 50% F(2:1 flax:olive oil) / 30% C (2:1:0.5 corn starch:sucrose:bran.  (I'll use HFFO)
3. High-fat lard/corn oil diet:   23% P (casein) / 50% F (1.8:1 lard:corn) / 27% C (sucrose).  (I'll use HFLC)

The study lasted 4-5 weeks, and although this timeframe was not long enough for a significantly greater increase in body weight for HF's vs. controls:

"... the omental, epididymal, and retroperitoneal fat depots were significantly greater in the high-fat diet-fed groups than in the chow-fed group (7.7 vs. 12.2g). The high-fat diet-fed rats had higher serum FFA levels than the chow-fed animals (756 vs. 249 μM)."

All of the increased fat depots are visceral fat, and I note the NEFA levels tripled for the high fat diets.

In our previous study of the effect of raising FFA on mitochondrial biogenesis in skeletal muscle, we fed rats a high-fat diet and gave them daily injections of heparin to raise serum FFA to high levels ... to mimic the effects of exercise on FFA levels. One purpose of the present study was to determine whether the more modest increase in FFA that results from feeding a high-fat diet also induces an increase in muscle mitochondria.   

They observed an increase in mitochondrial proteins in the muscles of HFFO rats vs. SC at 5 weeks accompanied by a significant increase in palmitic acid oxidation in skeletal muscle (17.8 for HF vs. 10.2 for SC units: nmol/min/g) that is evidence for increased functional mitochondria.  They also observed an increase in mitochondrial DNA.  Feeding HFLC -- e.g. altering the fatty acid content of the diet to 32% lard -- also produced the increases in muscle mitochondria.

Further, the HFFO diet also induced IR (of muscles, as evidenced by reduced muscle glucose transport).  Thus,

Because the high-fat diet-induced increases in mitochondria and in the capacity to oxidize fat occurred during the period in which insulin resistance developed, the muscle insulin resistance is clearly not due to mitochondrial deficiency.

And from the Discussion:

The major findings of the first phase of this study are that feeding rats high-fat diets results in an increase in mitochondria and in the capacity of muscle to oxidize fat concomitant with development of muscle insulin resistance. It has been hypothesized that skeletal muscle insulin resistance is mediated by a mitochondrial deficiency that limits fat oxidation and results in accumulation of intramyocellular lipids. This concept is based on the finding that muscles of insulin-resistant individuals generally contain  30% less mitochondria than those of insulin-sensitive control subjects. This phenomenon has also been referred to as mitochondrial dysfunction, although a detailed evaluation has provided evidence that the remaining mitochondria function normally. The present findings seem incompatible with the concept that muscle insulin resistance is mediated by mitochondrial deficiency. ...

... It is surprising that the mitochondrial deficiency causes insulin resistance concept has been so widely accepted, because it seems untenable in the context of what is known regarding the capacity of skeletal muscle for oxidative metabolism.  The mechanism by which a 30% decrease in muscle mitochondria has been proposed to cause muscle insulin resistance is an impairment in the ability to oxidize fat, resulting in accumulation of intramyocellular lipids. Actually, the rate of substrate oxidation in resting muscle is not determined/limited by mitochondrial oxidative capacity but by the rate of ATP breakdown/ADP formation, which is regulated by the cells’ need for energy.  The energy/substrate requirement of resting muscle cells is determined by ‘‘housekeeping’’ functions ... and is very low relative to the maximal capacity of muscle for substrate oxidation.   Increasing the supply of FFA or glucose to resting muscle can change the relative proportions of these substrates that are oxidized but does not result in an increase in substrate oxidation above that required to supply the energy needed for ATP repletion, regardless of its content of mitochondria.

This seems consistent with what leptin does in obesity which is to stimulate fatty acid oxidation.  Further, obesity is accompanied by an increased delivery of fatty acids to cells, contrary to the "starving cells myth".  The IR measured by reduced glucose uptake in obese and/or diabetic seems wholly consistent with the fact that the cells are forced to burning more fatty acids thus needing/burning less glucose, reducing clearance rate from plasma.  Perhaps the build-up of metabolites from the increased "turnover" w/o an accompanying increase in energy needs results in a bit of inefficiency where fats are not oxidized as cleanly and fully.  The association of IR with ceramides and/or diacylglycerols in cells would be consistent with this theory.

My thoughts on this whole mitochondrial dysfunction -- whatever that may actually be -- is more the result of diet and/or a condition such as diabetes or obesity, rather than the cause.