High-Fat Diet Causes Mitochondrial Dysfunction as a Result of Impaired ADP Sensitivity

Abstract

Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased mitochondrial protein expression; however, absolute mitochondrial respiration and ADP sensitivity were impaired across a range of biologically relevant ADP concentrations. In addition, HF consumption attenuated the ability of ADP to suppress mitochondrial HO emission, further suggesting impairments in ADP sensitivity. The abundance of ADP transport proteins were not altered, but the sensitivity to carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in adenine nucleotide translocase (ANT) ADP sensitivity in these observations. Moreover, palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in ADP sensitivity. Altogether, these data suggest that an HF diet induces mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial ADP sensitivity that is magnified by palmitoyl-CoA.

Supplementation with dietary ω‐3 mitigates immobilization‐induced reductions in skeletal muscle mitochondrial respiration in young women

“…If anything, there was a marginal trend for improved ADP sensitivity following immobilization in the control group using 2 independent experiments (i.e., apparent Km and the ability for ADP to suppress ROS rates), which we postulate is a potential compensatory response in an attempt to maintain energy homeostasis in the presence of reduced mitochondrial capacity that was not required following v-3 supplementation. In contrast to other models that exhibit reductions in ADP sensitivity (21,22), the lower VDAC/ANT proteins in addition to mitochondrial subunits following 2 wk of immobilization may require an increased affinity for ADP in order to maintain energy homeostasis. This could be related to the drastic nature of muscle disuse as opposed to prolonged stressors such as aging (21), the development of diabetes (32), and high dietary fat consumption (22).…”

“…In contrast to other models that exhibit reductions in ADP sensitivity (21,22), the lower VDAC/ANT proteins in addition to mitochondrial subunits following 2 wk of immobilization may require an increased affinity for ADP in order to maintain energy homeostasis. This could be related to the drastic nature of muscle disuse as opposed to prolonged stressors such as aging (21), the development of diabetes (32), and high dietary fat consumption (22). Together, these data further support the ability for mitochondria to adapt in terms of ADP responsiveness in the presence or absence of a reduction in mitochondrial capacity while highlighting the practical importance of v-3 supplementation prior to and during short periods of muscle disuse.…”

“…Mitochondrial oxphos capacity is known to influence mitochondrial responsiveness to ADP, and impaired ADPstimulated respiration is associated with aging (21), diabetes (32), and high dietary fat consumption (22) in parallel with compromised cellular homeostasis. As a result, ADP transport into the mitochondrial matrix has been implicated as a key molecular event influencing optimal mitochondrial bioenergetics (20).…”

“…This could be beneficial in the context of disuse atrophy because the movement of ADP into the mitochondrial matrix, and the subsequent binding of ADP to the F 0 F 1 adenosine triphosphate (ATP) synthase, stimulates oxidative phosphorylation (oxphos) and decreases ROS production (20), a signal known to activate atrophic pathways (18). Moreover, the observation that attenuated ADP sensitivity has been associated with redox stress during aging (21), and following the consumption of a high-fat diet (22) further supports the notion that mitochondrial ADP responsiveness is required for optimal cellular health.…”

Decrement in resting and insulin‐stimulated soleus muscle mitochondrial respiration is an early event in diet‐induced obesity in mice

“…Therefore, other mechanisms might be playing important roles and affecting the results obtained here. Also, it is important to note that Miotto, LeBlanc & Holloway (2018) showed, in red gastrocnemius, a reduction in ADP sensitivity after 28 days of HFD in C57/BlJ6 mice, suggesting that muscles with different fibre-type compositions could respond in different ways to lipid overload. Phielix et al (2014) demonstrated insulin resistance at the mitochondrial level by showing that obese insulin-resistant and T2DM patients were not able to increase O 2 flux after insulin stimulation.…”