The identification of brown/beige adipose tissue in adult humans has motivated the search for methods aimed at increasing its thermogenic activity as an approach to treat obesity. In rodents, the brown adipose tissue is under the control of sympathetic signals originating in the hypothalamus. However, the putative connection between the depots of brown/beige adipocytes and the hypothalamus in humans has never been explored. The objective of this study was to evaluate the response of the hypothalamus and brown/beige adipose tissue to cold stimulus in obese subjects undergoing body mass reduction following gastric bypass.
We evaluated twelve obese, non-diabetic subjects undergoing Roux-in-Y gastric bypass and 12 lean controls. Obese subjects were evaluated before and approximately 8 months after gastric bypass. Lean subjects were evaluated only at admission. Subjects were evaluated for hypothalamic activity in response to cold by functional magnetic resonance, whereas brown/beige adipose tissue activity was evaluated using a (F 18) fluorodeoxyglucose positron emisson tomography/computed tomography scan and real-time PCR measurement of signature genes.
Body mass reduction resulted in a significant increase in brown/beige adipose tissue activity in response to cold; however, no change in cold-induced hypothalamic activity was observed after body mass reduction. No correlation was found between brown/beige adipose tissue activation and hypothalamus activity in obese subjects or in lean controls.
In humans, the increase in brown/beige adipose tissue activity related to body mass reduction occurs independently of changes in hypothalamic activity as determined by functional magnetic resonance.
The hypothalamus has an important role in the control of whole-body energy homeostasis.1, 2, 3 In obesity, hypothalamic neurons are damaged by inflammatory signals triggered in response to dietary fats, resulting in defective control of caloric intake and energy expenditure.4, 5, 6 Adaptive thermogenesis is one of the physiological responses to increased caloric intake that can be affected by diet-induced hypothalamic inflammation.7, 8, 9 In rodents, uncoupled respiration in brown adipose tissue (BAT) accounts for a considerable fraction of thermogenesis and approaches aimed at increasing BAT activity can alleviate obese phenotypes.10, 11
Adult humans also have clusters of thermogenic active adipose cells characterized by a remarkably high uptake of glucose, which renders them easily detectable by (18F)-FDG PET scan.12, 13, 14 At first, based on their microscopic morphology and the expression of UCP1, it was proposed that these cells were collections of brown adipocytes.13, 14 However, recent refinement of gene profiling and the extended characterization of its ontogeny resulted in the identification of a new type of tissue, named beige adipose tissue.15 A recent study has shown that both brown and beige adipocytes coexist in most humans.16
Because of the beneficial metabolic effects of increased BAT activity in experimental models,17 it has been proposed that methods aimed at increasing the activity of brown/beige adipose tissue in humans could represent an interesting advance in the treatment of obesity and its comorbidities.18, 19 This possibility has motivated the search for pharmacological approaches aimed at stimulating the activity of brown/beige adipocytes. In rodents, BAT is activated by increased sympathetic tonus.20 Studies using a retrograde transsynaptic viral tracer identified ObRb-expressing neurons of the dorsomedial hypothalamus as the source of the sympathetic signals controlling BAT activity.21 However, in humans this is still a controversial issue.22 At least one study has shown that BAT of lean, but not obese subjects, can respond to pharmacological adrenergic stimulus.23 Conversely, other studies failed to demonstrate its activation raising the suspicion that mechanisms other than hypothalamic-generated sympathetic signals regulate the activity of brown/beige adipocytes.24, 25
To further explore this question, we employed functional magnetic resonance imaging (fMRI) in parallel with (F 18) fluorodeoxyglucose positron emisson tomography/computed tomography ((18F)-FDG PET/CT) scans and supraclavicular adipose tissue biopsies, to evaluate changes in hypothalamic and brown/beige adipose tissue activity in response to cold. Our subjects included normal weight controls and obese subjects undergoing body mass reduction as an outcome of Roux-in-Y gastric bypass (RYGB). We show that although body mass reduction resulted in a significant increase in the number of patients presenting cold-induced activation of brown/beige adipose tissue, this phenomenon was not accompanied by a significant change in hypothalamic neuronal activity. Thus, during body mass reduction in obese humans, brown/beige adipose tissue and the hypothalamus are independently regulated in response to cold.
Materials and methods
The study evaluated 12 obese females selected from the Obesity Clinic at the University of Campinas and 12 lean female control volunteers selected from the students of the University. The obese, non-diabetes-diagnosed subjects26 were included in the study after selection for bariatric surgery according to the standards of the National Institutes of Health Consensus Statement.27 Figure 1a presents a flowchart depicting the process of patient selection. Details of the selection are presented as Supplementary Data. The study was approved by the University of Campinas Ethics Committee (293/2011).
Overview of the experimental procedure
Once included, patients were submitted to a detailed nutritional evaluation and oriented for all behavioral changes required for the success of the surgical procedure. During the following 2–6 weeks, the patients were submitted to additional anthropometric evaluations, blood collection, fMRI and whole-body (18F)-FDG PET/CT scan. RYGB was always performed by the same surgeon who employed a technique previously described.28 During the surgery, specimens of ~2 cm3 were obtained from the abdominal subcutaneous and supraclavicular fat depots. The anatomical limits of the supraclavicular fat biopsy are depicted in Figure 1b. Approximately 8 months after surgery, the patients submitted to the same tests and procedures as before surgery. As surgical manipulation occurred only inside the abdomen during RYGB, we do not believe there could be any damage to the innervation of either abdominal or cervical adipose tissue that could interfere with the study. The lean controls submitted only once to a detailed nutritional and anthropometric evaluation followed by blood collection, (18F)-FDG PET/CT scan and fMRI.
In (18F)-FDG PET/CT scan, real-time PCR and fMRI studies, when comparing the means (and medians in real-time PCR) of the groups, we employed repeated-measure analysis of variance followed by Bonferroni post test. In fMRI studies, when comparing the means of signal intensity before and after cold exposure, we employed Student’s t-test for paired samples. Fisher’s exact test was employed to evaluate the activity of brown/beige adipose tissue, as determined by either (18F)-FDG PET/CT scan or real-time PCR. Spearman’s correlation rank was employed to determine the concordance between hypothalamic and brown/beige adipose tissue activity. In all analyses, the value of P<0.05 was defined as statistically significant.
Body mass reduction resulted in changes in anthropometric and metabolic parameters
As expected, ~8 months after RYGB, the patients presented significant reductions of body mass/body mass index, waist and hip circumferences, plasma insulin and serum triglyceride levels (Supplementary Table S1). However, body mass/body mass index, and waist and hip circumferences were still significantly higher than the lean controls (Supplementary Table S1).
Increased brown/beige adipose tissue activity after body mass reduction
Figure 1 illustrates the procedure for patient selection (Figure 1a) and the region of neck where biopsies were performed for evaluation of brown/beige markers (Figure 1b). Figure 2 shows representative images of (18F)-FDG PET/CT scans obtained from two obese subjects before and ~8 months after RYGB, and also from a lean control subject. As shown in Figure 3a, only 1 out of the 12 obese subjects was positive for brown/beige adipose tissue activity before surgery, whereas four turned into positive following body mass reduction. The obese patient that scored positive before surgery remained positive after surgery. Concerning the lean controls, 5 out of 12 were positive for brown/beige adipose tissue activity at the time of the examination. To determine the significance of these records, we initially used Fisher’s exact test to evaluate a contingency table prepared with the qualitative data of obese patients before surgery versus lean subjects and obese subjects after surgery versus lean subjects. Brown/beige adipose tissue positivity was higher in lean subjects as compared with obese patients before surgery (P=0.06; odds ratio=7.8). The comparison of obese patients after surgery versus lean subjects resulted in no significant difference (P=0.50; odds ratio=1.42). In addition, we analyzed the quantitative data using analysis of variance, which confirmed the results (Figure 3a). Thus, although obese patients were significantly less capable of activating brown/beige adipose tissue on cold exposure, the body mass reduction following bariatric surgery resulted in an increased capacity to activate brown/beige adipose tissue, resulting in numbers similar to lean controls. As differences in core temperature could influence brown/beige adipose tissue activity, we evaluated glucose uptake by skeletal muscle, which also is affected by core temperature.30, 31, 32 As depicted in Figure 3b, no differences in gluteus muscle standardized uptake value were detected. This is in accordance with a recent study, which showed that there is no change in core temperature in humans exposed to at 18 °C.33 Figure 3c depicts images from (18F)-FDG PET/CT scans illustrating the region of the gluteus used to measure muscle standardized uptake value. As environmental temperature is a major factor regulating brown/beige adipose tissue activity, we included a graph depicting the mean temperatures in the region of Campinas, Brazil, during the time this study was carried out (Supplementary Figure S1) and the approximate date when each patient/control was submitted to the examination.
Body mass reduction results in increased expression of brown/beige adipose tissue markers in supraclavicular adipose tissue
Tissue samples collected from the abdominal wall of obese patients during surgery exhibited only typical white adipocytes, whereas samples collected from the supraclavicular region exhibited clusters of adipocytes with a brown/beige phenotype surrounded by typical white adipocytes (Figure 4a). UCP1 could be detected by immunofluorescence staining in samples collected from the supraclavicular region, both before and after surgery (Figure 4b). Typically, UCP1 was detected at higher intensity of staining and in a larger number of cells in specimens collected after surgery, as compared with samples collected before surgery. No staining for UCP1 could be detected in samples from the abdominal wall (not shown). RNA samples were tested for the expression of a panel of adipocyte genes. In all patients, adipose tissue collected from the supraclavicular region tested positive for most of the brown/beige markers, whereas samples collected from the abdominal white adipose tissue tested negative or presented very low levels for most of the markers. White adipose tissue markers, HOXC9, KLF4 and NCOA, were predominantly expressed in the adipose tissue collected from the abdominal wall (Figure 4c). As depicted in Figure 4d, in samples from the supraclavicular region, UCP1, CITED, TMEM26, TBX1, ATXN1, BMP7 and PDGFRA underwent a significant increase following body mass reduction. Conversely, ZIC2 expression was significantly reduced following body mass reduction. For statistical analysis, we considered that BAT/beige adipose tissue scored positive whenever four or more markers of BAT/beige tissue (UCP1, CITED, TMEM26, TBX1, ATXN1, BMP7 and PDGFRA) were detected in levels threefold or higher than the levels detected in white adipose. Using these data, we compared the presence of brown/beige adipose tissue with the qualitative data obtained from the (18F)-FDG PET/CT scans, scoring the patients as concordant when both PCR and (18F)-FDG PET/CT scans presented similar results and discordant otherwise. A contingency table was constructed (Supplementary Table 2) and submitted to Fisher’s exact test evaluation, which revealed that the methods coincided to detect the presence of brown/beige adipose tissue (P=0.50).
No change in hypothalamic neuronal activity following body mass reduction
Immediately after exposure to cold, lean subjects presented an abrupt reduction in the signal detected during the fMRI temporal analysis of hypothalamic function (Figure 5a). For statistical purposes, we calculated the mean value of the signal during the 5 min that preceded the exposure to cold and during the 5 min subsequent to the beginning of cold exposure. A detailed view of the period used to calculate the means of the signal is shown in Figure 5b. A comparison of the means of the signal before and after cold exposure confirmed the significance of the change (Figure 5c). Employing the same method as described above for lean subjects, we evaluated the hypothalamic signal intensity in the obese subjects before surgery. As depicted in Figure 5d, there was no change in signal intensity after the exposure to cold. Again, we calculated the means of signal intensity before and after cold exposure (Figure 5e) and submitted the means to statistical analysis. As revealed in Figure 5f, the obese subjects before surgery presented no significant change in their hypothalamic response to cold. Approximately 8 months after bariatric surgery, the obese patients submitted to a second round of fMRI. As shown in Figure 5g, there was no apparent change in the hypothalamic responsiveness to cold. This was confirmed by calculating the means of the signals before and after cold exposure (Figure 5h), and submitting them to statistical analysis (Figure 5i). The mean change in signal intensity caused by cold exposure was significantly greater in lean subjects as compared with that in obese subjects, either before or after body mass reduction (Figure 5j). The approximate dates when patients and controls performed the fMRIs are shown in a graph depicting the environmental temperatures during the period of the study (Supplementary Figure 2).
No correlation between hypothalamic and brown/beige adipose tissue activity in response to cold
Qualitative and quantitative analysis were employed to evaluate the putative correlation between hypothalamic and brown/beige adipose tissue activity in response to cold. Initially, based on the magnitude of change in the fMRI signal intensity in the hypothalamus, subjects were scored either positive or negative for cold-induced activation of hypothalamic neurons. As depicted in Supplementary Table 3, three patients scored positive before surgery and four scored positive after surgery; only two patients that scored positive before surgery maintained positivity after surgery. In addition, correlation analysis comparing brown/beige adipose tissue activity as determined by the (18F)-FDG PET/CT scans and hypothalamic responsiveness to cold revealed no significance for either group: obese before surgery (r=0.32, P=0.30), obese after surgery (r=-0.04, P=0.89), or lean (r=0.33, P=0.29) (Figure 6).
The recent identification of brown/beige adipose tissue in adult humans12, 13, 14 has motivated the search for methods of increasing its activity as an alternative approach to bariatric surgeries to treat obesity and its comorbidities.18, 34 Because of its similarity with rodent BAT, which is under sympathetic control, sympathomimetic drugs were interesting candidates; however, at least two recent studies were unable to demonstrate the activation of human brown/beige adipose tissue by different β-adrenergic drugs.24, 25 Vosselman et al.24 treated lean subjects with the non-selective β-adrenergic agonist, isoprenaline, and compared its effects with cold exposure. Although isoprenaline was capable of increasing metabolic activity to levels similar to cold exposure, this outcome was not correlated with increased brown/beige adipose tissue activity.24 Likewise, Cypess et al.25 employed another non-selective adrenergic drug, ephedrine, which reproduced some of the outcomes of cold exposure, but again failed to stimulate brown/beige activity. Nevertheless, the importance of adrenergic activity to control human brown/beige adipose tissue is demonstrated by the fact that the non-specific β-blocker, propranolol, is capable of reducing glucose uptake by adipose tissue during (18F)-FDG PET/CT scans35, 36 and by a study on which ephedrine was capable of inducing BAT activity in lean, but not obese subjects.23
Several hypotheses have been proposed to explain this seemingly discordant data: one possibility is that the systemic levels obtained by the administration of sympathomimetic drugs are not sufficient to reach the synaptic concentration required to activate brown/beige adipose tissue in humans.25 Another possibility is that during drug-induced brown/beige adipose tissue thermogenesis, free fatty acids rather than glucose may be the preferred substrate, making the uptake of (18F)-FDG a non-optimal method for this evaluation.24 In addition, as signature genes for both brown and beige adipose tissues can coexist in the supraclavicular region of humans,16 it could be that the brown component is responsive to β-adrenergic stimulation, whereas the beige component is not, rendering the methods currently used insufficient to detect small changes in thermogenic activity.
Considering that at least part of the cold-induced thermogenic activity of human brown/beige adipose tissue is under sympathetic control, the most obvious origin for the innervating fibers would be the hypothalamus.20, 21 Development of neuroimaging methods has provided the means to reliably study the structure and function of the human hypothalamus.37, 38 At least two recent studies have shown changes in hypothalamic structure and function in human obesity.39, 40 On body mass reduction, only part of the hypothalamic defect in response to a nutrient stimulus is recovered,39 suggesting that, as in experimental animals,4, 5, 6 obese humans have severe and perhaps only partially reversible damage to the hypothalamic neurons involved in the control of whole-body energy homeostasis.
In the present study, we hypothesized that if the activity of the brown/beige adipose tissue were under hypothalamic control, changes in brown/beige adipose tissue occurring as a result of body mass reduction would be paralleled by changes in hypothalamic function. To test this hypothesis, we used an fMRI protocol developed for the evaluation of brain functionality in response to glucose,38 which was recently adapted for the evaluation of changes in hypothalamic activity in obese subjects.39 Here, instead of using a nutrient stimulus, we acutely exposed the subjects to a cold environment. The results obtained from the fMRI studies were then compared with brown/beige adipose tissue activity evaluated by (18F)-FDG PET/CT scans and with the expression of signature genes in biopsies from the supraclavicular fat depot.
Concerning the hypothalamus, we showed that lean but not obese subjects present a significant change in the cold-induced neuronal activity that occurs few seconds after exposure to a reduced environmental temperature. Although we have no knowledge of previous studies that evaluated the time course of changes in neuronal activity in humans exposed to cold, experimental animals submitted to low environmental temperatures present a rapid increase in c-fos expression in the hypothalamus, thus providing strong support for the existence of an immediate communication pathway between peripheral thermosensors and hypothalamic neurons.41 In addition, we showed that following body mass reduction, the hypothalamic activity in response to cold is not significantly modified. If this were true for the majority of obese humans undergoing body mass reduction, it means that an important mechanism involved in the control of whole-body energy homeostasis could be severely and, perhaps, irreversibly damaged in obesity. Interestingly, the responsiveness of hypothalamic neurons to glucose, which is also affected in obesity,39 is at least in part recovered after body mass reduction. Thus, we suggest that obesity affects neurons that are involved in the response to nutrients and to cold stimulus differently. There are two methodological issues that deserve additional comments. First, it is worth mentioning that the fMRI signals in subjects responding to cold stimulus underwent a negative variation. fMRI detects the signals produced by changes in the blood oxygen levels. The increasing firing rate of neurons increases the demand for oxygen, thus leading to vasodilation, which results in increased regional concentration of oxyhemoglobin. In the hypothalamus, there are distinct subpopulations of neurons that control thermogenesis. NPY/AgRPergic neurons fire to reduce thermogenesis, whereas POMC/CARTergic neurons fire to increase thermogenesis. We believe that the negative signal we detect in responsive subjects is due to the net result between activation and inactivation of these distinct subpopulations, prevailing the inhibition of firing of NPY/AgRPergic neurons and thus producing a negative fMRI signal. This brings us to the second issue, which refers to the spatial resolution of the method. Images were acquired to generate 3-mm voxels. This is expected to provide a resolution of about 1 cm. As the human hypothalamus is ~ cm3 large, the resolution of our fMRI allows for the detection of signals in the whole hypothalamus and not in specific nuclei. In the future, increased resolution of the method may allow for the definition of regions on which neurons are stimulated and regions on which neurons are inhibited by cold exposure.
Different from the hypothalamus, brown/beige adipose tissue activity, which was reduced in obese subjects as compared with that in lean subjects, presented a significant recovery after body mass reduction. Our results match the recently published data of Vijgen et al.,42 who evaluated 10 obese patients submitted to laparoscopic gastric banding surgery. Before the surgery, only two patients showed brown/beige adipose tissue activity, whereas five patients scored positive 1 year after the procedure.
In addition to (18F)-FDG PET/CT scans, we also evaluated the presence of brown/beige adipose tissue by the measurement of brown and beige adipose tissue signature gene expression in biopsies of supraclavicular fat. As previously reported,16, 43 we detected the presence of both classical BAT genes and some of the recently identified beige adipose tissue-specific genes. It is noteworthy that 7 out of 14 brown/beige mRNAs tested underwent significant increase following body mass reduction. However, both beige specific (TMEM and TBX1) and non-specific (UCP1, CITED, ATXN1, BMP7 and PDGFRA) mRNAs increased, suggesting that the depots of thermogenic adipocytes that can be stimulated on cold exposure and are recruited during body mass reduction are composed of both brown and beige cells.
The main objective of this study was to evaluate whether changes in the activity of brown/beige adipose tissue in response to cold would be accompanied by changes in the activity of hypothalamic neurons. We did not observe a significant correlation between subjects presenting increased brown/beige adipose tissue activity and hypothalamic responsiveness to cold in any group. In the obese group, this discordance was reinforced by the fact that after body mass reduction, there was an increase in the number of subjects presenting detectable brown/beige adipose tissue but no significant change in hypothalamic function. In the lean group, both brown/beige adipose tissue and hypothalamic activity were stimulated by cold exposure; however, no correlation was found between subjects presenting increased brown/beige adipose tissue and significant changes in hypothalamic activity. A recent study has shown that in lean, but not obese subjects, glucose metabolism in other regions of the brain, such as amygdala, occipital cortex and cerebellum, can be associated with increased BAT activity.44 Taken together, the results of the present study and the study by Orava et al.44 may suggest that either brown/beige adipose tissue is not under the control of the central nervous system or it is under the control of regions other than the hypothalamus.
In conclusion, this study demonstrates that obese subjects present a defective hypothalamic response to cold stimulation that is not recovered after body mass reduction. In addition, we did not detect any sign of connectivity between brown/beige adipose tissue and the hypothalamus, either in lean or in obese subjects.
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We thank E. Roman and G. Ferraz from the University of Campinas for technical assistance. Support for the study was provided by the Fundação de Amparo a Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico and grants from the Trust in Science Initiative from Glaxo-Smithkline, UK. The Laboratories of Cell Signaling and Experimental Endocrinology belong to the Obesity and Comorbidities Research Center and the National Institute of Science and Technology–Diabetes and Obesity.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on International Journal of Obesity website
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Rachid, B., van de Sande-Lee, S., Rodovalho, S. et al. Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity. Int J Obes 39, 1515–1522 (2015). https://doi.org/10.1038/ijo.2015.94
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