Abstract
Obesity is a prominent metabolic disease that predisposes individuals to multiple comorbidities, including type 2 diabetes mellitus, cardiovascular diseases, and cancer. Elevated circulating levels of fatty acids contribute to the development of obesity, in part, by targeting the hypothalamus. Palmitate, the most abundant circulating saturated fatty acid, has been demonstrated to dysregulate NAMPT and circadian clock proteins, as well as induce neuroinflammation. These effects ultimately result in hypothalamic dysregulation of feeding behavior and energy homeostasis. NAMPT is the rate-limiting enzyme of the NAD+ salvage pathway and its expression is under the control of the circadian clock. NAD+ produced from NAMPT can modulate the circadian clock, demonstrating bidirectional interactions between circadian and metabolic pathways. Using NPY/AgRP-expressing mHypoE-46 neurons as well as the novel mHypoA-BMAL1-WT/F and mHypoA-BMAL1-KO/F cell lines, we studied whether there were any interactions between NAMPT and the core circadian clock protein BMAL1 in the palmitate-mediated induction of neuroinflammation. We report that palmitate altered Nampt, Bmal1, Per2 and the inflammatory genes Nf-κb, IκBα, Il-6, and Tlr4. Contrary to studies performed with peripheral tissues, the palmitate-mediated induction in Nampt was independent of BMAL1, and basal Nampt levels did not appear to exhibit rhythmic expression. Palmitate-induced downregulation of Bmal1 and Per2 was independent of NAMPT. However, NAMPT and BMAL1 were both involved in the regulation of Nf-κb, IκBα, Il-6, and Tlr4, as NAMPT inhibition resulted in the repression of basal Nf-κb and IκBα and normalized palmitate-mediated increases in Il-6, and Tlr4. On the other hand, BMAL1 deletion repressed basal Nf-κb, but increased basal Il-6. We conclude that NAMPT and BMAL1 do not interact at the transcriptional level in hypothalamic neurons, but are independently involved in the expression of inflammatory genes.
Highlights
Obesity predisposes individuals to comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular diseases, and cancer [1]
Disruption of hypothalamic function by elevated saturated fatty acids is implicated in this disease as it affects peptidergic circuits that regulate feeding behavior and whole-body energy homeostasis
The ability of saturated fats to alter nicotinamide phosphoribosyltransferase (NAMPT) and the circadian clock as well as induce neuroinflammation has been suggested to contribute to hypothalamic dysfunction
Summary
Obesity predisposes individuals to comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular diseases, and cancer [1]. Increased consumption of fat is a main contributing factor to obesity [2], leading to elevated levels of saturated fatty acids (SFA) both in serum [3] and the hypothalamus [4]. The arcuate nucleus of the hypothalamus contains critical orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) and anorexigenic proopiomelanocortin (POMC) neurons. 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. Similar effects were observed in shift workers [16, 17] Saturated fats such as palmitate can alter the expression and rhythmicity of BMAL1, CLOCK, and PER2 to alter feeding peptide expression [6]
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