SUN-035 - Chemogenetic Silencing of Paraventricular Nucleus TRH Neurons Modulates Brown Adipose Tissue Thermogenic Gene Expression and Voluntary Wheel Running

The TRH hypophysiotropic neurons of the paraventricular nucleus (PVN) integrate metabolic signals and establish the set point of the hypothalamic-pituitary-thyroid (HPT) axis, regulating the release of thyrotropin-releasing hormone (TRH) and energy homeostasis. Voluntary wheel exercise increases Trh mRNA expression in the PVN compared to sedentary animals with paired feeding (PF). Furthermore, PVN-Trh expression and serum TSH and TH concentrations show a positive correlation with the distance covered in this model. These thyroid hormones activate brown adipose tissue (BAT), a metabolically active organ involved in thermogenesis, regulation of energy homeostasis, and immune responses.
To investigate the effects of inhibiting these neurons during voluntary exercise on BAT modulation in male Wistar-Han rats, we used the DREADD chemogenetic tool, evaluating serum levels of TSH, T3, T4, and IL-6 in the hMDGi4-TRH group compared to the Cre-TRH control. CNO was administered with euthanasia 2 h post-injection. The hMDGi4-TRH rats showed reduced serum levels of T3 and TSH compared to the Cre-TRH group, with no significant differences in T4 or IL-6. A decrease in the expression of the thermogenic genes Ucp1 and Adrb3 was observed in the BAT of the hMDGi4-TRH group compared to Cre-TRH.
In a second cohort, hMDGi4-TRH animals were administered CNO, and Cre-TRH animals received saline solution before access to voluntary wheel running during the dark period for 9 days; a sedentary PF group was included. Food intake, body weight, and distance covered were assessed; blood samples and BAT were obtained. Animals were sacrificed 3 h after the last exercise session to analyze serum parameters of the HPT axis and mRNA expression in BAT.
The hMDGi4-TRH/Ex group covered a greater distance compared to the Cre-TRH/Ex group. Furthermore, it showed reduced serum IL-6 levels compared to sedentary groups. Furthermore, BAT-Adrb3 mRNA increased significantly in the hMDGi4-TRH/Ex group compared to both sedentary groups. No significant changes were observed in Dio2, Pgc1a, or Ucp1.
In conclusion, inhibition of PVN-TRH neurons increases voluntary wheel running, possibly by altering locomotor or motivational capacity. Exercise activates sympathetic signaling in the BAT or alternative pathways that modulate adrenergic sensitivity, reflected in the increased expression of BAT-Adrb3, without inducing full thermogenic activation.

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