Role of the saturated fatty acid palmitate in the interconnected hypothalamic control of energy homeostasis and biological rhythms

Abstract

The brain, specifically the hypothalamus, controls whole body energy and glucose homeostasis through neurons that synthesize specific neuropeptides, whereas hypothalamic dysfunction is linked directly to insulin resistance, obesity, and type 2 diabetes mellitus. Nutrient excess, through overconsumption of a Western or high-fat diet, exposes the hypothalamus to high levels of free fatty acids, which induces neuroinflammation, endoplasmic reticulum stress, and dysregulation of neuropeptide synthesis. Furthermore, exposure to a high-fat diet also disrupts normal circadian rhythms, and conversely, clock gene knockout models have symptoms of metabolic disorders. While whole brain/animal studies have provided phenotypic end points and important clues to the genes involved, there are still major gaps in our understanding of the intracellular pathways and neuron-specific components that ultimately control circadian rhythms and energy homeostasis. Because of its complexity and heterogeneous nature, containing a diverse mix cell types, it is difficult to dissect the critical hypothalamic components involved in these processes. Of significance, we have the capacity to study these individual components using an extensive collection of both embryonic- and adult-derived, immortalized hypothalamic neuronal cell lines from rodents. These defined neuronal cell lines have been used to examine the impact of nutrient excess, such as palmitate, on circadian rhythms and neuroendocrine signaling pathways, as well as changes in vital neuropeptides, leading to the development of neuronal inflammation; the role of proinflammatory molecules in this process; and ultimately, restoration of normal signaling, clock gene expression, and neuropeptide synthesis in disrupted states by beneficial anti-inflammatory compounds in defined hypothalamic neurons.

NAMPT and BMAL1 Are Independently Involved in the Palmitate-Mediated Induction of Neuroinflammation in Hypothalamic Neurons

“…Specifically, NF-κB signaling is a key contributor to the deleterious effects of palmitate. For example, NF-κB inhibition was able to diminish the palmitatemediated increases in Npy and inflammatory gene expression (10,12,52). Our results demonstrate that NAMPT inhibition with FK866 had an anti-inflammatory effect, ablating the induction of Il-6 and Tlr4 mRNA by palmitate.…”

“…These neurons sense nutrients, such as fatty acids and peripheral hormones as signals of energy levels and release their respective neuropeptides to regulate energy homeostasis. Elevated SFA in the hypothalamus results in deleterious effects marked by the induction of neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, and circadian disruption, all of which can lead to hormonal resistance and neuropeptide dysregulation (5)(6)(7)(8)(9)(10)(11)(12).…”

Dietary n-6/n-3 Ratio Influences Brain Fatty Acid Composition in Adult Rats

“…Unfortunately, literature investigating region-specific effects of diet on brain PUFA composition is limited and more research is required to elucidate the time-course of these changes. Having said that, given that palmitate is generally positioned as a pro-inflammatory fatty acid [30], the current results may have implications for neuroinflammation in the HYP.…”

COMT-Catalyzed Palmitic Acid Methyl Ester Biosynthesis in Perivascular Adipose Tissue and its Potential Role Against Hypertension

“…Typically, PA is one of the most common saturated fatty acids found in the human body and can be obtained through diet and endogenous synthesis via de novo lipogenesis or lipolysis from triacylglycerol (TG) in adipose tissue. However, excess endogenous PA might induce endoplasmic reticulum stress (Tse et al, 2018) and lipotoxicity (Peng et al, 2011). It has been believed that degradation, desaturation and elongation of PA might be protective, and regulated by homeostasis mechanisms to prevent cells from lipid-related stress-induced damage (Green and Olson, 2011).…”