PPARs and the orchestration of metabolic fuel selection

Sugden, Mary C.; Zariwala, Mohammed Gulrez; Holness, Mark J.

doi:10.1016/j.phrs.2009.03.014

Cited by 52 publications

(40 citation statements)

References 127 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here, in accordance with the whole-body decrease in COX, there was a 40% decrease in hepatic PDC activity, with a concomitant 65% decrease in acetylcarnitine accumulation, which may be indicative of decreased hepatic PDC flux , Wall et al 2011. Importantly, the PDC is subject to both acute and chronic inhibition via PDK4, which phosphorylates and inhibits its activity (Sugden et al 2009). We have previously shown that selective upregulation of PDK4 and a concomitant inactivation of PDC in human skeletal muscle is linked to a decrease in insulin-stimulated glucose turnover and oxidation in metabolic states characterized by elevated lipid availability and insulin resistance ).…”

Section: Discussionsupporting

confidence: 60%

Dual effects of fibroblast growth factor 21 on hepatic energy metabolism

Samms

Murphy

Fowler

et al. 2015

Journal of Endocrinology

View full text Add to dashboard Cite

The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; nZ6) or recombinant human FGF21 protein (1 mg/kg per day; nZ6) for 14 days. FGF21 administration caused a 40% suppression (P!0.05) of hepatic pyruvate dehydrogenase complex (PDC), the ratelimiting step in glucose oxidation, a 34% decrease (P!0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P!0.05) in long-chain acylcarnitine content (an index of flux through b-oxidation) and a 47% reduction (P!0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (PDK4, a negative regulator of PDC), the phosphorylated (inhibited) form of acetylCoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria) and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1a) and sirtuin-1. These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.

show abstract

Section: Discussionsupporting

confidence: 60%

Dual effects of fibroblast growth factor 21 on hepatic energy metabolism

Samms

Murphy

Fowler

et al. 2015

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…It seems that affecting either the influx of FAs into the cell or their oxidation is still promising, despite debatable, therapeutic approaches. Both these aforementioned processes are tightly regulated by a set of nuclear receptors called peroxisome proliferator-activated receptors (PPARs) [9,10]. PPARγ coactivator 1-α (PGC-1α) is one of the best characterized regulatory proteins, and it interacts with numerous nuclear receptors (including PPARs) and regulates various aspects of cellular energy metabolism, mainly via the regulation of mitochondria number and functions [11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

The Role of PGC-1α in the Development of Insulin Resistance in Skeletal Muscle - Revisited

Łukaszuk

Kurek

Mikłosz

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Currently, obesity is a predominant medical condition and an important risk factor for the development of several diseases, including type 2 diabetes mellitus. Importantly, most research has indicated lipid-induced insulin resistance in skeletal muscles is a key link between the aforementioned pathological conditions. PGC-1α is a prominent regulator of myocellular energy metabolism orchestrating gene transcription programming in response to numerous environmental stimuli. Moreover, it is widely acknowledged that mitochondrial metabolism (primary metabolic target of PGC-1α) disturbances are widely acknowledged contributors to type 2 diabetes development. Therefore, it seems surprising that the exact physiological contribution of PGC-1α in the development of insulin resistance in skeletal muscle remains poorly understood. This review aims to reconcile these allegedly different findings by looking for a common denominator in the role(s) of PGC-1α in respect to lipid-induced insulin resistance in skeletal muscle. Our scrutiny of the literature indicates that interventions at the level of PGC-1α may exert beneficial effects on myocytes in respect to lipid-induced insulin resistance. The latter takes place as a result of a positive net energy balance (fatty acids oxidation surpassing their accumulation rate). Moreover, the aforementioned effects may not necessarily be limited to physically active states. They seem to occur, however, only within a physiologically observed range in muscle cells (approximately 1-fold changes in PGC-1α protein expression).

show abstract

“…Along these lines, the nuclear receptors PPARs (α,β/δ and γ) are able to regulate energy metabolism, and have a crucial role controlling the partition of nutrients (such as glucose and lipids) as metabolic fuels [13,14]. Both PPARα and β/δ are key in controlling fatty acid oxidation, and although PPAR β/δ shows greater expression in muscle, both are important in the control of muscle cell energy metabolism [13,14].…”

Section: Introductionmentioning

confidence: 99%