High Fat Diet Upregulates Fatty Acid Oxidation and Ketogenesis via Intervention of PPAR-γ

Abstract

Background/Aims: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis. Methods: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ^-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and lipid profiling, immunoblot, qPCR and immunohistochemistry (IHC) analysis of PPAR-γ and following mitochondrial metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), mitochondrial β- hydroxy butyrate dehydrogenase (BDH1) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In vivo model was translated in vitro, with neonatal rat cardiomyocytes (NRCM) treated with PPAR-γ agonist/antagonist and PPAR-γ overexpression adenovirus in presence of palmitic acid (PA). Apoptosis was determined in vivo from left ventricular heart by TUNEL assay and immunoblot analysis. Results: We found exaggerated circulating ketone bodies production and expressions of the related mitochondrial enzymes HMGCS2, BDH1 and PDK4 in HFD-induced diabetic hearts and in PA-treated NRCM. As a mechanistic approach we found HFD mediated activation of PPAR-γ is associated with the above-mentioned mitochondrial enzymes. HFD-fed PPAR-γ^-/-mice display decreased hyperglycemia, hyperlipidemia associated with increased insulin responsiveness as compared to HFD-fed WT mice PPAR-γ^-/–HFD mice demonstrated a more robust functional recovery after diabetes induction, as well as significantly reduced myocyte apoptosis and improved cardiac function. Conclusions: PPAR-γ has been described previously to regulate lipid metabolism and adipogenesis. The present study suggests for the first time that increased PPAR-γ expression by HFD is responsible for cardiac dysfunction via upregulation of mitochondrial enzymes HMGCS2, BDH1 and PDK4. Targeting PPAR-γ and its downstream mitochondrial enzymes will provide novel strategies in preventing metabolic and myocardial dysfunction in diabetes mellitus.

A high fat diet with a high C18:0/C16:0 ratio induced worse metabolic and transcriptomic profiles in C57BL/6 mice

“…Further pathway analysis showed that the common pathways possibly regulated by C16:0 and C18:0 include cytokine-cytokine receptor intervention, prolactin signaling pathway, retinol metabolism, fatty acid degradation, peroxisome, steroid hormone biosynthesis, PPAR signaling pathway, and arachidonic acid metabolism. These pathways have been found to be mostly involved in glucose and lipid metabolism [35][36][37][38], in accordance with the common biological processes found between the LSF group and the HSD group. These results indicate that the similarity in biological functions and mechanisms between C16:0 and C18:0 are mainly in relation to glucose and lipid metabolism, in which they act as substrates in metabolism, and the chain length is probably a key factor in determining their effects.…”

The impact of a high-fat diet in mice is dependent on duration and age, and differs between muscles

“…Here, we showed that a HFD caused an increase in the oxidative capacity (reflected by the SDH-OD) in muscles from young-adult but not old mice. The increase in skeletal muscle oxidative capacity with HFD has been previously reported in young-adult rodents (Eshima et al, 2017;Garcia-Roves et al, 2007;Hancock et al, 2008;Li et al, 2016b;Miller et al, 1984;Sikder et al, 2018;Thomas et al, 2014;Turner et al, 2007). Interestingly, it has been reported that the expression of enzymes in the citric acid cycle, β-oxidation and respiratory chain is comparable to that with standard diet after 2 weeks of HFD, but similarly elevated after 8 and 16 weeks of a HFD (Sadler et al, 2012).…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…Prolonged ketosis is also associated with upregulation of NAD + [75,82,121,122]. Increased levels of NAD + explain the upregulation of the histone deacetylases sirtuin-1 (SIRT-1) and SIRT-3 seen in the brains and peripheral tissues of animals fed a KD, as SIRTs are NAD + -dependent enzymes [123][124][125].…”