Abstract
BackgroundProlonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance. However, even 3 days of HFD consumption has been linked to inflammation within the key homeostatic brain region, the hypothalamus.MethodsMice were fed either a low-fat diet (LFD) or HFD containing 10% or 60% (Kcal) respectively from fat for 3 days. Mice were weighed, food intake measured and glucose tolerance calculated using intraperitoneal glucose tolerance tests (IPGTT). Proteomic analysis was carried out to determine if hypothalamic proteins were changed by a HFD. The direct effects of dietary fatty acids on mitochondrial morphology and on one of the proteins most changed by a HFD, dihydropyrimidinase-related protein 2 (DRP-2) a microtubule-associated protein which regulates microtubule dynamics, were also tested in mHypoE-N42 (N42) neuronal cells challenged with palmitic acid (PA) and oleic acid (OA).ResultsMice on the HFD, as expected, showed increased adiposity and glucose intolerance. Hypothalamic proteomic analysis revealed changes in 104 spots after 3 days on HFD, which, when identified by LC/MS/MS, were found to represent 78 proteins mainly associated with cytoskeleton and synaptic plasticity, stress response, glucose metabolism and mitochondrial function. Over half of the changed proteins have also been reported to be changed in neurodegenerative conditions such as Alzheimer’s disease. Also,in N42 neurons mitochondrial morphology and DRP-2 levels were altered by PA but not by OA.ConclusionThese results demonstrate that within 3 days, there is a relatively large effect of HFD on the hypothalamic proteome indicative of cellular stress, altered synaptic plasticity and mitochondrial function, but not inflammation. Changes in N42 cells show an effect of PA but not OA on DRP-2 and on mitochondrial morphology indicating that long-chain saturated fatty acids damage neuronal function.
Highlights
Prolonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance
The changed proteins were found to be mainly associated with the cytoskeleton and synaptic plasticity (37 spots corresponding to 25 proteins), cellular stress responses (32 spots corresponding to 22 proteins), glucose metabolism (14 spots corresponding to 10 proteins)
Many of the proteins changed in the present study have been associated with neurodegenerative diseases, Alzheimer’s disease (49 proteins) (Table 1 and Fig. 2)
Summary
Prolonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance. A number of studies in rodents on a HFD have shown inflammation in the hypothalamus, activating both microglia and astrocytes, via the toll like receptor 4 (TLR4) [8, 9] and IKKB/NFκB inflammatory pathway, resulting in leptin and insulin insensitivity [10, 11]. The importance of this pathway is underlined by the fact that blocking or inhibiting diet-induced hypothalamic inflammation prevents leptin insensitivity, glucose intolerance and obesity [10, 12, 13]. HFD-induced mitochondrial dysfunction may be the origin of hypothalamic dysfunction and inflammation with excessive dietary intake leading to mitochondrial overload and oxidative stress activating the NFκB inflammatory pathway [15]
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