Thermal lesions of the SCN do not abolish all gene expression rhythms in rat white adipose tissue, NAMPT remains rhythmic

Abstract

Obesity and type 2 diabetes mellitus are major health concerns worldwide. In obese-type 2 diabetic patients, the function of the central brain clock in the hypothalamus, as well as rhythmicity in white adipose tissue (WAT), are reduced. To better understand how peripheral clocks in white adipose tissue (WAT) are synchronized, we assessed the importance of the central brain clock for daily WAT rhythms. We compared gene expression rhythms of core clock genes (Bmal1, Per2, Cry1, Cry2, RevErbα, and DBP) and metabolic genes (SREBP1c, PPARα, PPARγ, FAS, LPL, HSL, CPT1b, Glut4, leptin, adiponectin, visfatin/NAMPT, and resistin) in epididymal and subcutaneous white adipose tissue (eWAT and sWAT) of SCN-lesioned and sham-lesioned rats housed in regular L/D conditions. Despite complete behavioral and hormonal arrhythmicity, SCN lesioning only abolished Cry2 and DBP rhythmicity in WAT, whereas the other clock gene rhythms were significantly reduced, but not completely abolished. We observed no major differences in the effect of SCN lesions between the two WAT depots. In contrast to clock genes, all metabolic genes lost their daily rhythmicity in WAT, with the exception of NAMPT. Interestingly, NAMPT rhythmicity was even less affected by SCN lesioning than the core clock genes, suggesting that it is either strongly coupled to the remaining rhythmicity in clock gene expression, or very sensitive to other external rhythmic factors. The L/D cycle could be such a rhythmic external factor that generates modulating signals by photic masking via the intrinsic photosensitive retinal ganglion cells in combination with the autonomic nervous system. Our findings indicate that in normal weight rats, gene expression rhythms in WAT can be maintained independent of the central brain clock.

Exposure to dim light at night alters daily rhythms of glucose and lipid metabolism in rats

“…Despite the attenuated rhythmicity of the central oscillator and its hormonal outputs after exposure to dim ALAN, the daily oscillations of clock genes in the liver and adipose tissue were largely preserved with only small changes in their acrophases or amplitudes ( Bmal1, Per1, Nr1d1 ). Our data are in line with other models with a disturbed central oscillator, also showing maintained daily clock gene rhythms in the liver and adipose tissue, which were often phase-advanced ( Husse et al, 2014 ; Kolbe et al, 2016 ; Kolbe et al, 2019 ; Van Der Spek et al, 2021 ). This phenomenon is observed only under the LD regime and not in constant darkness, suggesting an important role for behavioral and endocrine rhythms in the synchronization of peripheral clocks.…”

“…One of the assumed mechanisms is the regulation via PPARγ:SIRT1 complex ( Han et al, 2010 ); therefore, the misbalanced metabolic state could be one of the factors contributing to the loss of Sirt1 rhythmicity. NAMPT is an important enzyme in the NAD + salvage pathway ( Reinke and Asher, 2019 ; Van Der Spek et al, 2021 ). ALAN rats showed a tendency towards a phase-advanced Nampt rhythm, which could be explained by the shift of Bmal1 expression since the heterodimer CLOCK:BMAL1 promotes its transcription ( Lee and Kim, 2013 ).…”

“…This enzyme promotes CRY degradation and controls the transcription of nicotinamide phosphoribosyltransferase ( Nampt ) through its effects on the clock ( Lee and Kim, 2013 ). Nampt is a key player in the salvation of nicotinamide adenine dinucleotide (NAD + ) ( Reinke and Asher, 2019 ; Van Der Spek et al, 2021 ), the cofactor of sirtuin 1 (SIRT1). SIRT1, with the help of NAD + , deacetylates enzymes of catabolic processes but also affects the main loop of the molecular clock ( Nakahata et al, 2008 ; Levine et al, 2020 ).…”