Although brown adipose tissue (BAT) was discovered in mammals already in 1551 as well as in humans in 1902, the first systematic description of its distribution in humans was proven with autopsies in 1972 (Heaton, 1972). For a long time, BAT was believed to have no physiological relevance in adult humans (Nedergaard et al., 2007; Cypess et al., 2009; Virtanen et al., 2009). However, different research groups proved the contrary (Nedergaard et al., 2007; Cypess et al., 2009; Virtanen et al., 2009; van Marken Lichtenbelt et al., 2009). Recently, BAT has been attracting increasing interest of researchers (Saito et al., 2020) through different fields of biological and medical sciences including cell and molecular biology (Chen and Pfeifer, 2017; Claflin et al., 2022), endocrinology (Villarroya et al., 2017; Sentis et al., 2021), metabolic science (Alcalá et al., 2019; Yang and Stanford, 2022; Ziqubu et al., 2023) and neurosciences (Partonen, 2015; Ortiz-Alvarez et al., 2022; Sideromenos et al., 2022b).

Brown adipose tissue plays a key role in adaptive non-shivering thermogenesis and resting energy expenditure (Emmett et al., 2017; Chondronikola and Sidossis, 2019). Moreover, it is involved in metabolic homeostasis, regulating body weight, glucose and lipid metabolism (Rui, 2017; Sustarsic et al., 2018). In addition, recent research has shown that BAT act as an endocrine organ and interacts with the central nervous system (Villarroya et al., 2017; Martins et al., 2022; Till et al., 2022). BAT is also involved in circadian system (Yang et al., 2011; Meng et al., 2023), and its overactivation might contribute to the manifestation of mood disorders (Partonen, 2015), be a potential endophenotype of depression (Partonen, 2013) and contribute to a higher suicide risk (Holopainen et al., 2014).

In the following, the physiology of BAT as well as interactions between BAT, circadian clock, exogen factors like seasonality or drugs, and their impact on the risk of suicide will be reviewed. Furthermore, a potential link between body mass index (BMI), BAT dysregulation and suicide risk will be briefly discussed.

Both white and brown adipose tissue contribute to the regulation of food intake and energy turnover. While white adipose tissue stores energy, brown adipose tissue produces heat. By that, BAT contributes to the maintenance of body temperature during cold exposure and to the elevated core temperature during several behavioral states, including wakefulness, the acute phase response (fever), and stress (Morrison and Madden, 2014).

Fat cells (adipocytes) in BAT contain a high density of mitochondria with a specific protein, called uncoupling protein 1 (UCP1), which uncouples oxidation from ATP synthesis and converts glucose and fat acids into heat (Chen et al., 2022). BAT is under neuronal, hormonal and immune control (Rui, 2017; Sentis et al., 2021; Till et al., 2022). Furthermore, nutritive aspects can modulate its function. While capsaicin, caffeine (Van Schaik et al., 2022), rutin (Cheng et al., 2022) or unsaturated long chain fatty acids (Fosch et al., 2023) stimulate the BAT thermogenesis, food additives or pesticides (Wang et al., 2021) as well as saturated fat (Fosch et al., 2023) can inhibit the thermogenesis in BAT.

The predominant neural pathway and main trigger of BAT thermogenesis is the sympathetic pathway via beta-2 adrenergic receptor in human BAT (Straat et al., 2023), in rodents via β3-adrenergic receptor signaling (Cero et al., 2021). Stress leads to an increase thermogenesis in BAT via sympathetic activation. Neurons in dorsomedial hypothalamus receive a stress-related excitation from the dorsal peduncular cortex and dorsal tenia tecta in the ventromedial prefrontal cortex (Blessing et al., 2006; Nakamura and Morrison, 2022). Furthermore, BAT is modulated by ventromedial hypothalamus as well as by orexin, a neuropeptide produced in lateral hypothalamus (Martins et al., 2016). Orexin plays an important role in feeding and arousal as well as regulates also body temperature and energy homeostasis (Madden et al., 2012). Orexin deficiency in narcolepsy type 1 is associated with obesity due to impaired BAT thermogenesis, despite reduced food intake (Sellayah et al., 2011).

BAT secrets signaling molecules, called batokines, including peptides, metabolites, lipids, or microRNAs (Yang and Stanford, 2022) with autocrine, paracrine or endocrine function. To this group of batokines belong among others Interleukin 6, Myostatin, Neuregulin 4, Fibroblast Growth Factor 21 or Vascular Endothelial Growth Factor A (Martins et al., 2022). BAT can be thus considered as one of stress-responsive endocrine organs (Qing et al., 2020).

Physiological and behavior functions are rhythmic, regulated via endogenous pacemakers—circadian clocks. Wake and sleep cycles, body (core) temperature, hormone secretion, food intake or metabolic processes belong to the main circadian (about 24 h) rhythm. The central pacemaker (“central clock”) is located in the hypothalamic suprachiasmatic nucleus (SCN). The molecular mechanism of the circadian clock in mammals is generated by a cell-autonomous transcriptional autoregulatory feedback loop. The core clock genes include “clock circadian regulator,” aka circadian locomotor output cycles kaput (Clock), its analog “neuronal pas domain protein 2” (Npas2) and “basic helix–loop–helix ARNT like 1, aka brain-and-muscle ARNT-like protein 1” (Bmal1)—which encode activators; as well as period circadian regulators (Per1, Per2, Per3) and cryptochrome circadian regulators (Cry1 and Cry2)—which encode repressors (Takahashi, 2017; Bolsius et al., 2021).

The central clocks orchestrate all other clocks in the organism. All tissues, including WAT and BAT show circadian rhythmicity, which means, they have their own “clocks.” The circadian axis hypothalamus-adipose tissue emphasizes the importance of functional adipose tissue clock for the circadian regulation of energy homeostasis (Heyde et al., 2021) and its disruption can affect metabolic processes (Dollet and Zierath, 2019). Furthermore, circadian rhythm of core temperature can modulate the amplitude of circadian gene expression (Goh et al., 2021). Expression of core clock genes in brown fat, but not in white fat, is highly responsive to cold exposure (Li et al., 2013). Cryptochromes react not only to light exposure and ultraviolet radiation, but also to geomagnetic activity, and they take part in the energy balance involving BAT in mammals (López et al., 2010; Foley et al., 2011; Partonen, 2015).

BAT is associated with lower BMI and lower visceral obesity (Takeda et al., 2023) and regulates glucose metabolism and insulin sensitivity (Stanford et al., 2013). This is a rationale for the view that BAT can be considered a potential target to treat obesity and its comorbidities (Martins et al., 2022).

In obese individuals, BAT mass and activity are minimized due to reduced cell proliferation and preadipocyte differentiation and increased apoptosis (Alcalá et al., 2019). Changes in BAT (hypertrophy and whitening, disturbances of batokines) are described also in diabetes type two in rodents (Ziqubu et al., 2023).

In a prospective study of over 45,000 men, the suicide mortality rate was strongly inversely related to BMI, even when adjusted for medical illness, dietary factors, antidepressant use, physical activity, and social support (Mukamal et al., 2007).

A retrospective analysis on 387 people who died by suicide demonstrated a significant association between BMI decrease within the last 12 month and increased risk for suicide after adjustment for demographic characteristics, mental disorders, and comorbidities (Hecht et al., 2021). Furthermore, suicide attempters with mood disorders exhibit less adiposity, expressed as a reduced BMI, waist circumference and serum triglycerides, when compared to non-attempters (da Graça Cantarelli et al., 2015).

However, the findings are inconsistent Overweight/obesity was significant associated with the risk of suicidal ideation and suicide attempts among adolescents in low and middle income countries (Zhang et al., 2022). Furthermore, some authors point out that body weight has a complex relationship with physical and mental health including suicidal thoughts and behavior, which may not be possible to accurately capture with a singular metric such as BMI (Harris et al., 2022).

Studies from both the Northern and the Southern hemisphere in both mid-latitude and sub-tropical climate type report a seasonal pattern for suicides with a late spring/summer peak in suicide rates (Christodoulou et al., 2012; Dixon and Kalkstein, 2018). A review of 45 studies from 26 different countries confirmed those patterns (Galvão et al., 2018). Moreover, the seasonal variation is stronger for violent suicide (Christodoulou et al., 2012). Bioclimatic factors (sunlight exposure and global sunlight radiation, ambient temperature, precipitations) are considered to play a role in the seasonality of suicide (Christodoulou et al., 2012).

There is solid evidence of association between ambient temperature and its change and suicidality. Marion et al. showed that a combination of cooler preceding 3 months together with a warmer current month (both with a difference of 2.5°C) was associated with an increase of 30% in elderly suicide rate (Marion et al., 1999). Furthermore, there is a significant correlation between suicidality and rapidly increasing temperature (Volpe et al., 2008). This finding was further corroborated by analysis, showing that warm temperatures, especially abnormally warm temperatures during cool months, increased the risk for suicide (Kaufman and Fitzmaurice, 2021). This is congruent with earlier findings from a large population based study analyzing more than 250,000 deaths by suicide (Holopainen et al., 2014). Two peaks within a year could be found one main in May, the second one, less pronounced, in October. In the studied latitude, temperature changes from April to May as well as the temperature drop from September to October coincided with the seasonal suicide maximums in May and October. The authors could show that in May, the temperature difference between current and precedent month was the highest within the year, in line with the highest suicide risk (Holopainen et al., 2014).

In another study, large changes in solar insolation between winter and summer were associated with an increased risk of suicide attempts in bipolar 1 disorder (Bauer et al., 2021). Further, suicide rate was higher on days after a short-term increase in air temperature on the day before as well as on days with a lower cloud cover (higher insolation) in analysis focusing on both cloud cover and temperature changes (Schneider et al., 2020). More daylight due to natural conditions like summer at high latitude does seem to play a subordinate role, as there was only minimal increases in suicide rate (by 0.75%) for each extra hour of daylight increase within Norwegian regions (Hernæs and Skyrud, 2022).

The inhibition of brown adipogenesis by atypical or second-generation antipsychotics (SGA) is believed to be one possible mechanism to explain weight gain induced by SGA (Oh et al., 2012; Kristóf et al., 2016). Some first-generation antipsychotics like chlorpromazine can also reduce emotional hyperthermia, while non-dopaminerg mechanism of action has been suggested (Blessing et al., 2017). Weight gain and inhibition of BAT are common for SGA’s. However, clozapine shows the greatest effect among all SGA’s. In mouse brown adipocytes, both clozapine and quetiapine downregulated the brown adipogenesis, quetiapine being weaker than clozapine, whereas ziprasidone did not alter the differentiation. Clozapine also significantly inhibited the mRNA expression of lipogenic genes as well as adiponectin (Oh et al., 2012). In patients with schizophrenia, the treatment with SGA aripiprazole or clozapine was associated with a decreased BAT activity (measured by plasma levels of bone morphogenetic protein 8b, a batokine secreted by BAT), as compared to drug-free patients, and the decrease was more significant for clozapine compared to aripiprazole (Chen et al., 2022).

There is evidence suggesting also specific effects of clozapine on BAT, compared to other SGA’s. Expression of UPC1 was elevated by clozapine, but not with six other antipsychotics in human adipocytes ex vivo, leading to an induction of beige cells rather than the classical brown phenotype (Kristóf et al., 2016). The relevance of this finding remains unclear. However, clozapine relevantly reduces stress-induced thermogenesis in BAT and might be effective in life-threatening hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA, aka ecstasy) in humans (Blessing et al., 2006). Another proposed mechanism is a blockage of thermogenic effects of orexin by clozapine (Monda et al., 2004).

There are only few studies concerning the effects of lithium on adipocytes. There is evidence that lithium can downregulate the brown adipocyte differentiation (Rodríguez de la Concepción et al., 2005). However, low-dose lithium chloride leads to an inhibition of glycogen-synthase kinase and thus to a beiging-like effect in WAT obtained from mice (Geromella et al., 2022). This finding can be compared to a similar effect of clozapine, i.e., induction of beige cells from white adipocytes (Kristóf et al., 2016).

Summarizing the above presented findings, we present following hypothesis that would need to be confirmed by experimental studies:

The best way to measure volume and activity of BAT is the use of 18 [F]-Fluorodeoxyglucose (18-F-FDG) in combination with a positron emission tomography/computed tomography (PET/CT). Second, as periphery biomarkers, UPC-1, or BAT-derived exomes can be used (Giralt et al., 2016; Chen and Pfeifer, 2017; Alito et al., 2022). Batokines have already been discussed above, however, they are not BAT-specific. Third, the assessment of the supraclavicular skin temperature using thermal sensors as promising non-invasive measures (e.g., iButtons) was related to cold-induced 18-F-FDG in women (Martinez-Tellez et al., 2019). However, it is not established yet as an alternative to 18-F-FDG yet.

In summary, we suggest that BAT pathophysiology plays a potential role in psychiatric conditions and deserves more attention in neurosciences. The recent study on beta-adrenergic profile in human BAT compared to rodents (Straat et al., 2023) pointed out the need for more studies in human population.

Understanding which combination of environmental and endogenous factors, and under which conditions increase suicide risk, may contribute to a better prevention of suicide. Figure 2 presents an overview of suicide risk factors, including those where the involvement of BAT is likely or assumed as well as the role of lithium and clozapine. Whether or not BAT activity is elevated in individuals with suicidal ideation and behavior, remains to be seen in experimental studies. One way to find this out would be to measure BAT activity (direct or indirect assessment). The time spent in the natural ambient temperature can vary, not only between regions and cultures, but also between individuals and might be associated with life standards. Since humans actively regulate their ambient temperature, mid-term assessment of BAT activity together with the monitoring of the (individual) ambient temperature would be one possible experimental design. Thus, one potential study design could implement measurements of individual ambient temperature when assessing the impact of meteorological conditions or seasonal patterns of mood or behavior. Monitoring changes in BAT activity under therapy with rapid acting antidepressants, lithium, or clozapine would be an example of one plausible study design to address clinical aspects.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

JS, TP, and UL contributed to conception of the manuscript. JS wrote the first draft of the manuscript, supervised by UL. TP contributed to literature and conclusions and reviewed all figures. All authors substantially contributed to the manuscript revision, read and approved the submitted version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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