Both linoleic and linolenic acid prevent insulin resistance but have divergent impacts on skeletal muscle mitochondrial bioenergetics in obese Zucker rats

The therapeutic use of polyunsaturated fatty acids (PUFA) in preserving insulin sensitivity has gained interest in recent decades; however, the roles of linoleic acid (LA) and alpha linolenic acid (ALA) remain poorly understood. We investigated the efficacy of diets enriched with either LA or ALA on attenuating the development of insulin resistance (IR) in obesity. Following a 12 wk intervention, LA and ALA both prevented the shift toward an IR phenotype and maintained muscle-specific insulin sensitivity otherwise lost in obese control animals. The beneficial effects of ALA were independent of changes in skeletal muscle mitochondrial content and oxidative capacity, as obese control and ALA-treated rats showed similar increases in these parameters. However, ALA increased the propensity for mitochondrial H2O2 emission and catalase content within whole muscle and reduced markers of oxidative stress (4 HNE and protein carbonylation). In contrast, LA prevented changes in markers of mitochondrial content, respiratory function, H2O2 emission, and oxidative stress in obese animals, thereby resembling levels seen in lean animals. Together, our data suggest that LA and ALA are efficacious in preventing IR but have divergent impacts on skeletal muscle mitochondrial content and function. Moreover, we propose that LA has value in preserving insulin sensitivity in the development of obesity, thereby challenging the classical view that n6 PUFAs are detrimental. (Authors abstract)

Both linoleic and linolenic acid prevent insulin resistance but have divergent impacts on skeletal muscle mitochondrial bioenergetics in obese Zucker rats. The therapeutic
use of polyunsaturated fatty acids (PUFA) in preserving insulin sensitivity has gained interest in recent decades; however, the roles of linoleic acid (LA) and linolenic acid (ALA) remain poorly understood. This study investigated in young obese Zucker rats whether LA  and ALA enriched diets could prevent the expected age-related decline in glucose homeostasis. Skeletal muscle mitochondria exist in two spatially distinct subpopulations known as subsarcolemmal (SS) and the predominant intermyofibrillar (IMF) mitochondria. These subpopulations possess unique characteristics and respond differently to various metabolic perturbations in obesity and type 2 diabetes as well as changes in diet composition. Sub population specific responses of SS and IMF mitochondria to LA and ALA enriched diets and the necessity of adaptations within these mitochondria in mitigating IR were determined.  Following a 12 wk intervention, LA and ALA both prevented the shift toward an insulin resistance (IR) phenotype and maintained muscle specific insulin sensitivity otherwise lost in obese control animals. The beneficial effects of ALA were independent of changes in skeletal muscle mitochondrial content and oxidative capacity, as obese control and ALA treated rats showed similar increases in these parameters. The data suggest that LA and ALA are efficacious in preventing IR but have divergent impacts on skeletal muscle mitochondrial content and function. Moreover, the authors propose that LA has value in preserving insulin sensitivity in the development of obesity, thereby challenging the classical view that n 6 PUFAs are detrimental.

The current study shows that the development of IR in obesity can be prevented by dietary supplementation with LA and ALA. A moderate 10 per cent  isocaloric increase in either of these PUFA species was efficient in attenuating the impaired glucose homeostasis documented in a common genetic model of obesity and insulin resistance. These findings were associated with the conservation of skeletal muscle insulin signaling and oxidative stress relative to lean healthy animals. Examining aspects of mitochondrial dysfunction revealed that LA and ALA have markedly different impacts on SS mitochondrial ETC content and bioenergetics compared with IMF. This was further supported by ALA specific increases in maximal H2O2 emission in SS mitochondria as well as the expression of catalase. Overall, the current data support a beneficial link between ALA and insulin sensitivity and provide novel evidence that LA can prevent impairments in glucose homeostasis and skeletal muscle insulin sensitivity in a model of severe genetic obesity.

The current study provides insight on the link between ALA and insulin sensitivity and
evidence that LA supplementation represents additional therapeutic potential. Although aspects of mitochondrial dysfunction were very similar between obese control and ALA supplemented rats, the preservation of skeletal muscle insulin signaling and whole body glucose homeostasis highlights the value of this n 3 PUFA. The precise mechanism(s) by which LA and ALA exert their preserving effects requires further elucidation and may involve changes in liver given the enhanced glucose tolerance.  Future investigations should focus on changes in membrane phospholipid composition, as both n 3 and n 6 PUFA are known to compete in the remodeling of membranes, including mitochondria, and may also preferentially accumulate in different tissues. The impacts of LA and ALA on IR may transcend the boundaries of skeletal muscle and mitochondria but nevertheless represent valuable therapeutic strategies for preventing the development of an insulin resistant phenotype in obesity. (Editors comments)