title: Orexin A attenuates palmitic acid-induced hypothalamic cell death.
abstract: Palmitic acid (PA), an abundant dietary saturated fatty acid, contributes to obesity and hypothalamic dysregulation in part through increase in oxidative stress, insulin resistance, and neuroinflammation. Increased production of reactive oxygen species (ROS) as a result of PA exposure contributes to the onset of neuronal apoptosis. Additionally, high fat diets lead to changes in hypothalamic gene expression profiles including suppression of the anti-apoptotic protein B cell lymphoma 2 (Bcl-2) and upregulation of the pro-apoptotic protein B cell lymphoma 2 associated X protein (Bax). Orexin A (OXA), a hypothalamic peptide important in obesity resistance, also contributes to neuroprotection. Prior studies have demonstrated that OXA attenuates oxidative stress induced cell death. We hypothesized that OXA would be neuroprotective against PA induced cell death. To test this, we treated an immortalized hypothalamic cell line (designated mHypoA-1/2) with OXA and PA. We demonstrate that OXA attenuates PA-induced hypothalamic cell death via reduced caspase-3/7 apoptosis, stabilization of Bcl-2 gene expression, and reduced Bax/Bcl-2 gene expression ratio. We also found that OXA inhibits ROS production after PA exposure. Finally, we show that PA exposure in mHypoA-1/2 cells significantly reduces basal respiration, maximum respiration, ATP production, and reserve capacity. However, OXA treatment reverses PA-induced changes in intracellular metabolism, increasing basal respiration, maximum respiration, ATP production, and reserve capacity. Collectively, these results support that OXA protects against PA-induced hypothalamic dysregulation, and may represent one mechanism through which OXA can ameliorate effects of obesogenic diet on brain health.
authors.affiliation: Minneapolis Veterans Affairs Health Care System, Research 151, One Veterans Dr, Minneapolis, MN 55417, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA.
authors.forename: Cayla M
authors.initials: CM
authors.lastname: Duffy
authors.affiliation: Minneapolis Veterans Affairs Health Care System, Research 151, One Veterans Dr, Minneapolis, MN 55417, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Nixon
authors.affiliation: Minneapolis Veterans Affairs Health Care System, Research 151, One Veterans Dr, Minneapolis, MN 55417, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA; Minnesota Obesity Center, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA. Electronic address: butte017@umn.edu.
authors.forename: Tammy A
authors.initials: TA
authors.lastname: Butterick
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D019069:Cell Respiration; D007031:Hypothalamus / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000068797:Orexins / Q000494:pharmacology*; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D000068797:Orexins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019308:Palmitic Acid; D000255:Adenosine Triphosphate; D053148:Caspase 3; D053179:Caspase 7
keywords: Apoptosis; Hypocretin; Neurodegeneration; Neuroprotection; Palmitic acid; Reactive oxygen species