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.

The research was led by Professor Shigenobu Matsumura of Osaka Metropolitan University’s Graduate School of Human Life and Ecology. The team focused on neurons that express melanocortin-4 receptor, commonly known as MC4R. These neurons are located in the hypothalamus, a brain region that coordinates appetite, energy expenditure, body weight, temperature, and several other physiological functions. MC4R signaling is one of the central pathways involved in controlling body mass. When activated, it generally reduces food intake and promotes a state of greater energy use. Genetic or functional disturbances in this pathway have been associated with severe forms of obesity in both humans and experimental animals.

OPA1 is a protein found within mitochondria, the structures often described as the energy-producing units of cells. More specifically, OPA1 helps mitochondria maintain their internal architecture by promoting the fusion of mitochondrial membranes. This structural organization is essential for efficient energy production, regulation of cellular stress, and communication between metabolic pathways. Neurons have particularly high energy demands because they must maintain electrical gradients and continuously transmit signals. If mitochondrial function is impaired in appetite-regulating neurons, the resulting metabolic disturbance could alter how the brain interprets nutritional signals and controls feeding behavior.

To investigate that possibility, the researchers compared normal mice with genetically modified animals lacking OPA1 specifically in MC4R-expressing neurons. This neuron-specific approach allowed the team to examine the protein’s role in appetite regulation without eliminating OPA1 throughout the body, where it performs essential functions in many tissues. The animals were allowed to feed freely, and soybean oil was used as a dietary fat source. Rather than testing only a rigid, pre-measured diet, the free-feeding design enabled the researchers to observe how the mice voluntarily responded when fat was available as part of their food environment.

The results revealed a notable difference between male and female mice. In male wild-type animals, soybean oil increased the expression of OPA1, suggesting that dietary fat may trigger a mitochondrial adaptation in MC4R neurons. That response was not observed in females. The sex-specific pattern indicates that the neurons may process the metabolic consequences of dietary fat differently depending on biological sex. The researchers did not present the finding as evidence that OPA1 alone determines obesity, but it points to the protein as one component of a broader network connecting food composition, mitochondrial activity, neural signaling, and long-term body-weight regulation.

The consequences of removing OPA1 were especially striking over time. Mice without OPA1 in their MC4R neurons consumed more food and developed age-related weight gain, with obesity becoming more apparent as the animals grew older. When given access to both standard chow and soybean oil, the modified mice consumed more fat and gained additional weight. The effect was particularly pronounced in females, even though female wild-type mice did not show the same soybean-oil-associated increase in OPA1 expression seen in males. This apparent mismatch suggests that the absence of OPA1 may expose a vulnerability in female appetite-control circuits rather than simply preventing a protective response that occurs in males.

At the cellular level, the findings are consistent with the idea that mitochondria do more than supply energy. They also act as sensors and regulators of cellular conditions. Changes in mitochondrial fusion can influence the production of energy, reactive oxygen species, calcium handling, and the ability of neurons to respond to hormonal and nutrient-related signals. In MC4R neurons, such changes could affect the strength or timing of melanocortin signaling, potentially making the brain less effective at limiting food intake after energy needs have been met. The current study does not establish every step in that chain, but it provides experimental evidence that mitochondrial integrity within a defined neuronal population is linked to dietary-fat consumption and body-weight control.

The researchers also tested setmelanotide, a drug that activates MC4R and is used to treat certain forms of genetic obesity. In control male mice, the compound successfully suppressed appetite. It also reduced food intake in male mice lacking OPA1. In females, however, the appetite-suppressing effect was significantly weaker when OPA1 was absent from MC4R neurons. This result is important because it suggests that the effectiveness of an MC4R-targeting treatment may depend not only on whether the receptor is present, but also on the metabolic condition of the neurons that contain it. A receptor-activating drug may be less effective if the cellular machinery needed to translate that signal into sustained appetite control has been disrupted.

The study was conducted in mice, so its findings cannot yet be assumed to apply directly to people. Human appetite regulation involves numerous interacting systems, including hormones released by the gut and adipose tissue, reward pathways involved in food preference, sleep, stress, physical activity, and environmental access to calorie-dense foods. Soybean oil was also used as an experimental fat source and should not be interpreted as the sole cause of obesity in humans. Nevertheless, the work adds to growing evidence that dietary fat can influence the brain through mechanisms that extend beyond calorie intake alone. By identifying a link between OPA1, MC4R neurons, and sex-dependent responses to fat, the researchers provide a potential molecular target for future studies of personalized obesity therapies.

“Our findings provide key insights into the mechanisms underlying obesity from the perspective of neuronal energy metabolism,” Matsumura said. He added that the observed differences in OPA1 responses and obesity susceptibility could help guide treatments that account for sex-specific biology. Future research will need to determine how OPA1 is regulated in human appetite circuits, whether similar changes occur in people with obesity, and how mitochondrial dynamics interact with hormones and other signals that activate MC4R. The findings, published in The FASEB Journal, suggest that the battle against overeating may depend partly on the condition of microscopic energy systems inside the brain’s appetite-control neurons.

Subject of Research: Animals

Article Title: OPA1 in MC4R Neurons Regulates Dietary Fat Intake and Body Weight in Mice

News Publication Date: 21-May-2026

Web References: Osaka Metropolitan University, https://www.omu.ac.jp/en/

References: DOI: 10.1096/fj.202600452R

Image Credits: Osaka Metropolitan University

Keywords

OPA1, MC4R neurons, obesity, dietary fat, soybean oil, appetite regulation, mitochondria, hypothalamus, setmelanotide, body weight, sex differences, mice