Dataset Information

Developmental exposure to DDT or DDE alters sympathetic innervation of brown adipose in adult female mice.

ABSTRACT:

Background

Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis.

Methods

Pregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p'-DDT and o,p'-DDT) or DDE (p,p'-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated.

Results

We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p'-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p'-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p'-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p'-DDE, respectively, compared to control.

Conclusions

These data demonstrate that perinatal exposure to DDTs or p,p'-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

SUBMITTER: vonderEmbse AN

PROVIDER: S-EPMC8017793 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectiveThe objective of this study was to functionally analyze the correlation of key histological features in brown adipose tissue (BAT) with clinical metabolic traits in nonhuman primates.MethodsAxillary adipose tissue biopsies were collected from a metabolically diverse nonhuman primate cohort with clinical metabolism-related data. Expression of tyrosine hydroxylase (TH), uncoupling protein 1 (UCP1), cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX IV), beta-3 adrenergic receptor (β3-AR), and adipose cell size were quantified by immunohistochemical analysis. Computed tomography scans were performed to assess body composition.ResultsTyrosine hydroxylase was negatively correlated with whole body fat mass as a percentage of body weight (p = 0.004) and was positively correlated with the density of UCP1 (p = 0.02), COX IV (p = 0.006), CD31 (p = 0.007), and cell density (p = 0.02) of the BAT samples. Beta-3 adrenergic receptor abundance had a weak positive correlation with COX IV (p = 0.04) in BAT but did not significantly correlate to UCP1 or TH expression in BAT.ConclusionsOur findings highlight that there is a disparity in innervation provided to BAT based on body composition, as seen with the negative association between TH, a marker for innervation, and adiposity. These findings also support the importance of innervation in the functionality of BAT, as TH abundance not only supports leaner body composition but is also positively correlated with known structural elements in BAT (UCP1, COX IV, CD31, and cell density). Based on our observations, β3-AR abundance does not strongly drive these structural elements or TH, all of which are known to be important in the function of brown adipose tissue. In effect, while the role of other receptors, such as β2-AR, should be reviewed in BAT function, these results support the development of safe sympathetic nervous system stimulants to activate brown adipose tissue for obesity treatment.

Project description:BackgroundLow-frequency electroacupuncture (EA) has been shown to ameliorate obesity and reproductive dysfunctions in patients with polycystic ovary syndrome (PCOS), and further explorations in PCOS-like rats showed that EA could affect white adipose tissue. However, the function and neuromodulation of brown adipose tissue (BAT) in PCOS and after EA treatment have remained unknown. The present study focused on the role of BAT in PCOS-like rats and its relationship with EA and characterized the three-dimensional (3D) innervation of BAT associated with activation molecules.MethodsFemale rats (21 days old) were implanted with dihydrotestosterone or fed with a high fat diet to establish PCOS-like and obesity models, respectively, and then EA treatment at "Guilai" (ST 29) and "Sanyinjiao" (SP 6) was carried out for 4 weeks. In the present study, morphological analysis, 3D imaging, molecular biology, and other experimental techniques were used to study the sympathetic nerves and activity of BAT.ResultsPCOS-like rats showed both obvious weight gain and reproductive dysfunction, similar to what was seen in obese rats except for the absence of reproductive dysfunction. The body weight gain was mainly caused by an increase in white adipose tissue, and there was an abnormal decrease in BAT. Because both the lipid metabolism and reproductive disorders could be improved with bilateral EA at "Guilai" (ST 29) and "Sanyinjiao" (SP 6), especially the restoration of BAT, we further investigated the neuromodulation and inflammation in BAT and identified the sympathetic marker tyrosine hydroxylase as one of the key factors of sympathetic nerves. Modified adipo-clearing technology and 3D high-resolution imaging showed that crooked or dispersed sympathetic nerves, but not the twisted vasculature, were reconstructed and associated with the activation of BAT and are likely to be the functional target for EA treatment.ConclusionOur study highlights the significant role of BAT and its sympathetic innervations in PCOS and in EA therapy.