NUTR3360_Module 9_Role of Muscle in Metabolic Disease_Part 2

The role of muscle in developing metabolic complications is significant, particularly through the function of fatty acid transporters.

Accumulation of reactive lipid species like diacylglycerols (DAGs) and ceramides contributes to insulin resistance (not triglycerides).
Factors contributing to lipid accumulation in muscle:
- Increased fat uptake
- Reduced fat oxidation
Influences on fat levels in muscle:
- Increased non-esterified fatty acids (NEFA) due to lipolysis from adipose tissue.
- Production of very-low-density lipoproteins (VLDL) in the liver and their delivery to muscle.
- Import of NEFA across the plasma membrane (sarcolemma).
- Lipolysis of muscle TAG stores.
- Transport of fatty acids into mitochondria for beta-oxidation.
- Mitochondrial activity and number.

Adipose tissue and liver release NEFA transported in blood bound to albumin.
Fatty acid uptake mechanisms:
- Passive diffusion across the plasma membrane.
- Transport-mediated processes.

FAT/CD36 (Fatty Acid Translocase)
- Ubiquitously expressed and critical in fatty acid transport, validated by inhibitors and CD36 knockout mice models.
FABPpm (Fatty Acid Binding Protein, Plasma Membrane)
- Recognized as the first fatty acid transporter.
FATP4 (Fatty Acid Transport Protein)
- Least characterized among fatty acid transporters.

Insulin plays a role in regulating glucose and fat translocation to muscle.
Influences GLUT-4, a glucose transporter, involved in enhancing uptake of glucose with insulin signaling affecting FAT/CD36 as well.

Over-expression studies in rat muscle indicate increases in fatty acid uptake with all transporters; CD36 and FATP4 showed the most significant impact.
These findings suggest targeted strategies to enhance fatty acid uptake into muscle.

The presence of multiple fatty acid transporters raises questions about differing cellular fates for fatty acids.
Research on over-expression showed that transporters increase beta-oxidation without significantly altering TAG storage.

Examined effects of FAT/CD36 deficiency via knockout models in mice.
Findings showed increased levels of circulating non-esterified fatty acids without compensation from other transporters, highlighting the critical role of FAT/CD36.

Knocking out FAT/CD36 resulted in decreased fatty acid transport and oxidation in muscle.
Observed reductions in muscle TAG, DAG, and ceramides, leading to increased reliance on glucose for energy.

Questions arise on whether changes in muscle fatty acid handling contribute to metabolic dysfunction in obesity and type 2 diabetes (T2D).

Increased fat uptake into muscle correlates with obesity and T2D; more FAT/CD36 present at the plasma membrane.
Suggests a direct association between disease states and fatty acid transport processes.

Obesity and T2D are linked with increased esterification of fatty acids into TAG, raising levels of intramyocellular TAG.

Studies indicate fat oxidation declines in extreme obesity, although this is still debated in scientific literature.

Reduced cycling of FAT/CD36 leads to increased fatty acid uptake and esterification, while oxidation decreases in states of obesity and T2D.

Activation of AMPK promotes:
- Increased fatty acid oxidation and glucose uptake.
- Enhanced fatty acid uptake and synthesis.
- Decreased levels of DAGs and ceramides.

Exercise escalates fatty acid uptake through the elevation of FAT/CD36 levels in muscle.
Blocking FAT/CD36 function impairs exercise-induced increases in fatty acid uptake.

Exercise and insulin enhance glucose (GLUT4) and fatty acid (FAT/CD36) uptake through different signaling pathways.

Exercise facilitates fatty acid esterification while reducing DAGs and ceramides, indicating a beneficial metabolic effect.

FAT/CD36 plays a pivotal role in fatty acid uptake.
Increased fat storage and decreased fat utilization are notable in obesity and T2D.
Insulin signaling impacts GLUT4 and FAT/CD36 differently, with exercise having additive effects.