Brown adipose tissue, or BAT, is often described as the body’s biological furnace. Unlike white adipose tissue, which stores energy in the form of large lipid droplets, brown fat burns energy to generate heat, a process known as thermogenesis. This is accomplished largely through uncoupling protein 1, or UCP1, which short-circuits the mitochondrial proton gradient to release energy as heat rather than storing it as ATP. In humans, BAT activity declines with age and obesity, and reduced BAT function has been linked to impaired postprandial glucose clearance, meaning the body’s ability to handle blood sugar spikes after meals. This connection has fueled interest in BAT activation as a therapeutic target for metabolic disease.

The Zagreb team, led by Nikola Habek and Aleksandra Dugandžić, focused on uroguanylin, a peptide hormone that binds to guanylate cyclase C receptors and has previously been implicated in appetite regulation and gut-brain signaling. Uroguanylin is synthesized as an inactive precursor, proguanylin-like pro-uroguanylin (proUGN), which is then cleaved into its active form. While UGN’s role in the intestine is well characterized, its expression and function within the central nervous system, particularly in relation to thermoregulation, have remained poorly understood. The researchers set out to determine whether brain-derived UGN contributes to the regulation of BAT activity, and whether this contribution differs between the sexes.

To address this question, the team employed a multi-pronged experimental strategy. Brown adipose tissue activity was assessed using infrared thermography in wild-type C57Bl/6NCrl mice and UGN knockout littermates. BAT volume was measured using magnetic resonance imaging, while molecular markers associated with the “browning” of fat tissue were quantified using quantitative polymerase chain reaction. In parallel, the researchers measured proUGN expression in both mouse and human brain tissue using enzyme-linked immunosorbent assay, or ELISA. The inclusion of human tissue added a translational dimension often missing from preclinical metabolic studies.

One of the most striking findings emerged from the human brain analysis. In tissue obtained from human subjects, the researchers observed decreased proUGN expression in several brain regions, specifically the hypothalamus, Brodmann area 10, and Brodmann area 11, but only in male subjects with obesity. No comparable decrease was detected in female brain tissue. The hypothalamus is a well-established hub for autonomic control of BAT thermogenesis, receiving input from hunger and satiety circuits and sending sympathetic signals to brown fat depots via the spinal intermediolateral cell column. Brodmann areas 10 and 11, located in the prefrontal cortex, have been implicated in higher-order regulation of appetite and metabolic control. The male-specific reduction in proUGN in these regions suggests that obesity may disrupt a UGN-dependent pathway in a sexually dimorphic manner.

In mice, the relationship between feeding, brain UGN, and brown fat activation also proved to be sex-dependent. After a meal, brown adipose tissue normally increases its activity as part of diet-induced thermogenesis, helping to dissipate excess energy and support glucose disposal. The researchers found that this postprandial activation of BAT was linked to changes in hypothalamic proUGN expression, but this coupling was observed only in male mice. Female mice did not show the same pattern of hypothalamic proUGN regulation after eating, suggesting that the mechanism linking food intake to BAT activation through brain UGN operates differently, or possibly not at all, in females.

The role of the reproductive cycle added another layer of complexity. In female mice, the effects of centrally applied uroguanylin depended not only on sex but also on the phase of the estrous cycle. This finding is notable because it underscores a methodological concern that has gained increasing attention in neuroscience and metabolic research. Many laboratory studies, particularly those in rodents, historically used only male animals, partly to avoid variability attributed to the estrous cycle. The current study suggests that such variability is not mere noise but reflects genuine physiological regulation that could be clinically relevant for female patients.

The researchers also explored whether a GLP-1 analogue, a class of drugs that has transformed the treatment landscape for obesity and type 2 diabetes through medications such as semaglutide and liraglutide, could modulate brain UGN expression and BAT activity. In young male mice, intranasal administration of a GLP-1 analogue increased brown adipose tissue activity and decreased hypothalamic proUGN expression, but these effects were seen only in males. In both male and female mice, the GLP-1 analogue increased BAT activity, suggesting that GLP-1 receptor agonists engage thermogenic pathways through mechanisms that extend beyond UGN signaling, particularly in females. This observation points toward a completely different mechanism of GLP-1 action in the female brain and may help explain sex-dependent differences in clinical responses to these medications.

Chronic administration of uroguanylin itself produced another intriguing sex difference. When UGN was given repeatedly, postprandial BAT activation increased in both sexes, indicating that the hormone can indeed enhance brown fat thermogenic responses in males and females alike. However, an increase in total brown adipose tissue volume was observed only in male mice. Because BAT volume is a determinant of overall thermogenic and glucose-handling capacity, this finding implies that the long-term metabolic benefits of UGN-based interventions may be structurally different in males and females. In males, UGN appears capable of both activating existing brown fat and expanding the tissue itself, whereas in females, the effect appears limited to functional activation without tissue expansion.

The authors emphasize that the therapeutic implications of these findings are substantial. If brain-derived UGN regulates brown fat in a sex-dependent manner, then any attempt to harness this pathway for the treatment of obesity or type 2 diabetes must account for the patient’s sex. A UGN-based therapy that works well in men might produce blunted or entirely different effects in women, and vice versa. Similarly, the estrous-cycle dependence of UGN’s central effects in females raises the possibility that hormonal status, including menstrual cycle phase, hormonal contraceptive use, or menopause, could influence how women respond to BAT-targeting therapies. This kind of nuance has been historically overlooked in metabolic drug development, where clinical trials often enroll predominantly male participants or fail to stratify results by sex.

The study also raises fundamental questions about the biology of uroguanylin in the central nervous system. The finding that proUGN expression decreases in the hypothalamus and prefrontal cortex of men with obesity suggests that obesity may perturb a brain peptide system that is not typically considered part of the metabolic disease landscape. Whether this reduction is a cause or consequence of obesity, and whether it can be reversed through weight loss or pharmacological intervention, remains to be determined. The mouse data indicating that GLP-1 analogues can modulate hypothalamic proUGN expression adds an additional dimension, suggesting that some of the metabolic benefits of these blockbuster weight-loss drugs could be mediated, at least in part, through UGN-dependent pathways in males.

The Zagreb team’s work fits within a growing body of literature highlighting sex differences in metabolic physiology. Brown adipose tissue itself is known to differ between males and females in humans, with some studies suggesting higher BAT prevalence and activity in women. The neural circuits governing BAT thermogenesis, including hypothalamic and brainstem pathways, are also influenced by gonadal hormones such as estrogen and testosterone. By demonstrating that a specific brain peptide, uroguanylin, participates in this sexual dimorphism, the study provides a concrete molecular handle on a phenomenon that has long been recognized but poorly understood at the mechanistic level.

Looking ahead, the researchers suggest that the development of therapies targeting brain-activated brown fat must incorporate sex as a biological variable from the earliest stages of research and development. As the global burden of obesity and type 2 diabetes continues to grow, and as GLP-1 receptor agonists reshape expectations for pharmacological treatment, understanding the precise neural mechanisms through which these interventions work, and how they differ between men and women, will be critical for optimizing their use. The study by Habek, Ratko, Dugandžić, and colleagues represents an important step in that direction, revealing that one of the brain’s most overlooked peptides may play a central role in determining how our bodies burn the calories we consume.