Mechanisms Driving Palmitate-Mediated Neuronal Dysregulation in the Hypothalamus

Abstract

The hypothalamus maintains whole-body homeostasis by integrating information from circulating hormones, nutrients and signaling molecules. Distinct neuronal subpopulations that express and secrete unique neuropeptides execute the individual functions of the hypothalamus, including, but not limited to, the regulation of energy homeostasis, reproduction and circadian rhythms. Alterations at the hypothalamic level can lead to a myriad of diseases, such as type 2 diabetes mellitus, obesity, and infertility. The excessive consumption of saturated fatty acids can induce neuroinflammation, endoplasmic reticulum stress, and resistance to peripheral signals, ultimately leading to hyperphagia, obesity, impaired reproductive function and disturbed circadian rhythms. This review focuses on the how the changes in the underlying molecular mechanisms caused by palmitate exposure, the most commonly consumed saturated fatty acid, and the potential involvement of microRNAs, a class of non-coding RNA molecules that regulate gene expression post-transcriptionally, can result in detrimental alterations in protein expression and content. Studying the involvement of microRNAs in hypothalamic function holds immense potential, as these molecular markers are quickly proving to be valuable tools in the diagnosis and treatment of metabolic disease.

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

“…The highly vascularized hypothalamus responds to and transmits signals from feeding-related hormones, neuronal signals, and nutrients derived from the bloodstream (Velloso & Schwartz, 2011). As a “metabolic sensor”, the hypothalamus is vulnerable to overfeeding and obesity-related elevations in levels of plasma pro-inflammatory mediators including cytokines and saturated fatty acids (Lieu et al, 2021). Overfeeding also causes the blood-brain barrier to break down, further enabling inflammatory factors to access the central nervous system (Guillemot-Legris et al, 2016; Guillemot-Legris & Muccioli, 2017; Stranahan et al, 2016).…”

The Involvement of the microRNAs miR-466c and miR-340 in the Palmitate-Mediated Dysregulation of Gonadotropin-Releasing Hormone Gene Expression

“…Palmitate, a 16-carbon chain saturated fatty acid (C16:0), is the most prevalent fatty acid in the human body. It is increased after the consumption of an HFD or synthesized endogenously from other fatty acids, carbohydrates, and amino acids [6]. Palmitate is important for basal functions of the cell; however, excessive consumption, as seen in obese individuals, can lead to detrimental effects.…”

“…Palmitate is important for basal functions of the cell; however, excessive consumption, as seen in obese individuals, can lead to detrimental effects. The hypothalamus can sense these elevated circulating free fatty acids [7,8], which are associated with dysregulation in neuroendocrine signaling, circadian clock dysfunction, neuroinflammation, and endoplasmic reticulum stress [6]. Our laboratory has studied the effects of palmitate on many levels, including signal transduction events, detrimental cellular functions, and transcriptionally [6].…”

“…The hypothalamus can sense these elevated circulating free fatty acids [7,8], which are associated with dysregulation in neuroendocrine signaling, circadian clock dysfunction, neuroinflammation, and endoplasmic reticulum stress [6]. Our laboratory has studied the effects of palmitate on many levels, including signal transduction events, detrimental cellular functions, and transcriptionally [6]. A study by Tran et al demonstrated the upregulation of Gnrh mRNA by palmitate in the immortalized mHypoA-GnRH/GFP cell line [9].…”