PREreview of The Hypothalamic–Pituitary–Adrenal Axis Orchestrates Energy Homeostasis during Cold Exposure

Summary:

This study uncovers a previously unrecognized role of the hypothalamic-pituitary-adrenal (HPA) axis in orchestrating energy homeostasis during cold exposure. The authors demonstrate that exposure to cold activates the HPA axis, leading to the release of adrenocorticotropic hormone (ACTH) and glucocorticoids. The authors provide evidence that ACTH directly stimulates brown adipocyte thermogenesis via the melanocortin-2 receptor (MC2R), increasing energy expenditure. This hormonal pathway operates alongside sympathetic nervous system activation, coordinating a robust thermogenic response necessary for maintaining body temperature. Furthermore, the study identifies a dual function for glucocorticoids: they drive cold-induced hyperphagia to compensate for energy loss and act permissively to prevent desensitization of MC2R, thereby sustaining ACTH-mediated thermogenesis.

The study is strengthened by a comprehensive and carefully designed experimental strategy. By integrating in vitro, ex vivo, and in vivo approaches, alongside CRISPR-mediated gene editing and pharmacological tools. This work offers meaningful insights into how neuroendocrine systems coordinate metabolic adaptation, moving beyond the traditional view of the HPA axis as solely a stress response system. These findings have potential translational implications for understanding metabolic diseases such as obesity, by highlighting the complex interplay between thermogenesis and appetite control.

The writing throughout the article is clear, elegant, and accessible. The narrative flows smoothly, and the explanations allow readers from various backgrounds to follow the findings with ease.

Below, we propose some comments in order to improve the clarity and interpretation of the study.

Major Comments

In Figures 2E and 3C, the experimental groups appear to start at different baseline metabolic rates before the cold challenge/intervention. Comparing the total Area Under the Curve (AUC) in these instances can be misleading, as it captures the baseline difference rather than the specific response to the stimulus. Therefore, we suggest the authors replace the AUC by iAUC in these analyses.

We are curious about why, while the authors use ANCOVA for body weight changes (Fig 5A), the energy expenditure analysis appears to rely on AUC/t-tests. As detailed in consensus guidelines (e.g., Speakman, 2013; Banks et al., 2025) published by some of the authors of this paper, energy expenditure should be analyzed using ANCOVA with body weight / lean mass as a covariate. Since presenting raw EE or AUC without this adjustment can lead to erroneous conclusions, particularly in DIO models where body composition varies significantly, an explanation for this selection of analysis would improve the understanding of the readers.

While Figure 3F demonstrates that dexamethasone increases cumulative food intake, the corresponding energy expenditure data is absent. Given the paper’s central thesis, which is that ACTH drives thermogenesis while glucocorticoids drive intake, it is crucial to show whether dexamethasone affects energy expenditure.

One of the mechanistic aspects that could be developed further is whether neutralizing ACTH decreases energy expenditure at room temperature, not only during cold exposure.

The study utilizes a dosage of 1 mg/kg for ACTH injections. It is important to contextualize this dose. How does this compare to physiological circulating concentrations in mice during cold stress? Discussing the translational relevance of this dosage compared to human physiology would help clarify whether the observed effects represent a physiological adaptation or a pharmacological response.

Minor comments

To better understand how ACTH and glucocorticoids work inside brown adipocytes, this study could look more closely at the signaling pathways activated by each hormone. This includes examining how ACTH activates MC2R to increase cAMP/PKA signaling, changes in DAG and calcium, as well as exploring other possible pathways like MAPK or PI3K/Akt. Additionally, clarifying which specific thermogenic genes are regulated by the glucocorticoid receptor would provide a more complete picture of the intracellular mechanisms.

The discussion would benefit from a more explicit connection to human clinical scenarios. For example, how might energy balance be altered in patients with HPA axis disruptions (e.g., Cushing’s syndrome or adrenal insufficiency)?

A transparent discussion regarding potential confounding factors, such as systemic stress responses induced by the injection procedures themselves, would strengthen the rigor of the manuscript.

Some figure legends and labels are dense. We suggest simplifying the nomenclature and clearly indicating the duration of cold exposure directly on the figure panels to facilitate interpretation. In Figure 1C specifically, please clarify if the trace represents a single representative mouse or an average of the cohort.

In addition to cumulative food intake, presenting day-by-day feeding data would be valuable to reveal specific temporal patterns of energy regulation.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they did not use generative AI to come up with new ideas for their review.