Schnabl, K. | Search bioRxiv

bioRxiv2025

The Hypothalamic-Pituitary-Adrenal Axis Orchestrates Energy Homeostasis during Cold Exposure

Cold exposure stimulates the sympathetic nervous system (SNS) to activate brown fat thermogenesis and maintain optimal body temperature, while simultaneously triggering compensatory hyperphagia to restore energy balance. The mechanisms coordinating energy expenditure and intake, however, remain unclear. Here, we reveal that the hypothalamic-pituitary-adrenal (HPA) axis plays a dual role in this process: endogenous adrenocorticotropic hormone (ACTH) directly stimulates the melanocortin-2 receptor (MC2R) in brown adipocytes to promote thermogenesis, whereas glucocorticoids drive cold-induced hyperphagia and act permissively to enhance ACTH-mediated energy expenditure. These findings uncover previously unrecognized functions of the HPA axis and a delicate hormonal interplay that orchestrates energy homeostasis during cold stress. Targeting these pathways may offer novel strategies to mitigate hyperphagic responses associated with increased energy expenditure, with potential implications for obesity treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/677113v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1ac072forg.highwire.dtl.DTLVardef@10bc88corg.highwire.dtl.DTLVardef@9b9b5corg.highwire.dtl.DTLVardef@1f4e276_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe HPA axis orchestrates cold adaptation. C_LIO_LIACTH activates brown fat thermogenesis in vitro and in vivo via activating MC2R. C_LIO_LIGlucocorticoids drive cold-induced hyperphagia. C_LIO_LIGlucocorticoids have a permissive effect on ACTH function in brown adipocytes. C_LI

physiology↗

bioRxiv2022

Secretin modulates appetite via brown adipose tissue - brain axis

Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is unknown. In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]FDG-PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin down-regulated the brain response to appetizing food images and improved inhibitory control. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling pattern promoted satiation. These findings suggest that secretin modulates the BAT-brain metabolic crosstalk and subsequent neurometabolic coupling to induce satiation, bearing potential clinical benefits for treating eating disorders. Significance of the studySecretin activates brown adipose tissue and induces satiation, but the underlying brain mechanisms are still unclear. This placebo-controlled PET-fMRI study uses brain metabolic and BOLD measures to dissect the modulatory effects of secretin on brain functions associative to satiation. Findings show that secretin i) modulates caudate glucose metabolism via the BAT-brain axis, ii) enhances BOLD response in inhibitory control, and iii) reduces reward-related BOLD response. Further evidence shows that these measured effects are tightly linked via the secretin-mediated brain neurometabolic coupling. This study significantly advances our knowledge on how secretin leads to satiation and highlights the potential role of secretin in treating eating disorders and obesity.

neuroscience↗