Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight

  • Baishali Alok Jana
  • Pavan Kumar Chintamaneni
  • Praveen Thaggikuppe Krishnamurthy
  • Ashish Wadhwani
  • Suresh Kumar Mohankumar
Original Article


Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis. Several recent studies indicate that reduced insulin-stimulated ATP synthesis and reduced expression of mitochondrial enzymes and PPAR-γ coactivator, in high fat feeding (lipid overload) are associated with insulin resistance. Despite the fact, few notable studies suggest mitochondrial dysfunction is prevalent in type 2 diabetes mellitus; it is still not clear whether the defects in mitochondrial function are the cause of insulin resistance or the consequential effects of insulin resistance itself. Thus, there is a growing interest in understanding the intricacies of mitochondrial function and its association with cytosolic lipid excess. This review therefore critically examines the molecular cascades linking cytosolic lipid excess and mitochondrial dysfunction in the pathogenesis of high fat diet-induced insulin resistance in skeletal muscle.

Graphical abstract

The sequential processes following the excess intake of high fat diet in skeletal muscle includes, accumulation of cytosolic fatty acids, increased production of reactive oxygen species, mutations and ageing, and decreased mitochondrial biogenesis. The consequent mitochondrial dysfunction is then leading to decreased β-oxidation, respiratory functions and glycolysis and increased glucolipotoxicity. These events collectively induce the insulin resistance in skeletal muscle.


Cytosolic lipids Mitochondria Insulin resistance High fat diet Type 2 diabetes mellitus 


Author contributions

SKM conceived the idea, skeleton, draft editing and proof reading; BAC wrote the initial draft contributed to molecular mechanisms; PKC contributed to the pharmacology aspects and drafted graphical abstract; PTK and AW contributed to the editing and proof reading. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.


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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Baishali Alok Jana
    • 1
  • Pavan Kumar Chintamaneni
    • 2
  • Praveen Thaggikuppe Krishnamurthy
    • 2
  • Ashish Wadhwani
    • 1
  • Suresh Kumar Mohankumar
    • 3
  1. 1.Department of Pharmaceutical BiotechnologyJSS College of Pharmacy (A Constituent College of JSS Academy of Higher Education & Research, Mysuru, Karnataka, India)OotacamundIndia
  2. 2.Department of PharmacologyJSS College of Pharmacy (A Constituent College of JSS Academy of Higher Education & Research, Mysuru, Karnataka, India)OotacamundIndia
  3. 3.Department of Pharmacognosy & PhytopharmacyTIFAC CORE in Herbal Drugs, JSS College of Pharmacy (A Constituent College of JSS Academy of Higher Education & Research, Mysuru, Karnataka, India)OotacamundIndia

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