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The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue.

ABSTRACT: Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.

SUBMITTER: Wang B

PROVIDER: S-EPMC8397754 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

Project description:Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discovered that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impaired BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This was associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.

2021-07-19 | GSE178366 | GEO

The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

Project description:The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

| PRJNA738705 | ENA

Electrical Neurostimulation Promotes Brown Adipose Tissue Thermogenesis.

Project description:BackgroundBrown adipose tissue (BAT) is present in humans and rodents, and contributes to energy expenditure by converting energy stored in lipids and glucose into heat. Beta adrenergic receptor (β-AR) agonists have been proposed as pharmacological tools to activate BAT, but they lack selectivity for this tissue. This study aimed to investigate the possibility to apply electrical neurostimulation as a novel approach to activate BAT by promoting the sympathetic outflow towards BAT.MethodsMale C57BL/6J mice were treated with either unilateral electrical neurostimulation of interscapular BAT or with the β3-AR agonist CL316,243. Thermogenesis, nutrient uptake by BAT and downstream signaling of adrenergic receptors in BAT were examined.ResultsElectrical neurostimulation and β3-AR agonism acutely increased heat production by BAT, as evidenced by an increase in local temperature in BAT, without influencing the core body temperature. Both treatments acutely increased tyrosine hydroxylase content in the nerve terminals thereby confirming enhanced sympathetic activity. In addition, we identified increased phosphorylation of hormone-sensitive lipase coinciding with reduced intracellular lipids in BAT, without affecting acute nutrient uptake from plasma. The increased BAT temperature as induced by electrical neurostimulation was reversed by β3-AR antagonism.ConclusionElectrical neurostimulation acutely promotes thermogenesis in BAT as dependent on β3-AR signaling. We anticipate that electrical neurostimulation may be further developed as a novel strategy to activate BAT and thereby combat (cardio)metabolic diseases.

| S-EPMC7555256 | biostudies-literature

GPSM1 in POMC neurons impairs brown adipose tissue thermogenesis and provokes diet-induced obesity.

Project description:ObjectiveG-protein-signaling modulator 1 (GPSM1) has been proved the potential role in brain tissues, however, whether GPSM1 in hypothalamic nuclei, especially in POMC neurons is essential for the proper regulation of whole-body energy balance remains unknown. The aim of our current study was to explore the role of GPSM1 in POMC neurons in metabolic homeostasis.MethodsWe generated POMC neuron specific GPSM1 deficiency mice and subjected them to a High Fat Diet to monitor metabolic phenotypes in vivo. By using various molecular, biochemical, immunofluorescent, immunohistochemical analyses, and cell culture studies to reveal the pathophysiological role of GPSM1 in POMC neurons and elucidate the underlying mechanisms of GPSM1 regulating POMC neurons activity.ResultsWe demonstrated that mice lacking GPSM1 in POMC neurons were protected against diet-induced obesity, glucose dysregulation, insulin resistance, and hepatic steatosis. Mechanistically, GPSM1 deficiency in POMC neurons induced enhanced autophagy and improved leptin sensitivity through PI3K/AKT/mTOR signaling, thereby increasing POMC expression and α-MSH production, and concurrently enhancing sympathetic innervation and activity, thus resulting in decreased food intake and increased brown adipose tissue thermogenesis.ConclusionsOur findings identify a novel function of GPSM1 expressed in POMC neurons in the regulation of whole-body energy balance and metabolic homeostasis by regulating autophagy and leptin sensitivity, which suggests that GPSM1 in the POMC neurons could be a promising therapeutic target to combat obesity and obesity-related metabolic disorders.

| S-EPMC10698273 | biostudies-literature

Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.

Project description:Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts ?-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.

| S-EPMC5647161 | biostudies-literature

Adipose HIF-1? causes obesity by suppressing brown adipose tissue thermogenesis.

Project description:Hypoxia-inducible factor-1? (HIF-1?) in adipose tissue is known to promote obesity. We hypothesized that HIF-1? interferes with brown fat thermogenesis, thus decreasing energy expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1? in adipose tissues (HIF-1?++) at usual temperature (22 °C), where brown fat is somewhat active, or at thermoneutrality (30 °C), where brown fat is minimally active. HIF-1?++ mice or control litter mates were separated into room temperature (22 °C) or thermoneutrality (30 °C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 °C, HIF-1?++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1?++ mice, oxygen consumption decreased ~50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1?). In conclusion, adipose HIF-1? overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature. KEY MESSAGE:Constitutive HIF-1? activation in adipose tissue promotes weight gain in mice. The weight gain is associated with reduced brown adipose tissue function and oxygen consumption. Reduced oxygen consumption may be mediated by reductions in mitochondria.

| S-EPMC5322176 | biostudies-literature

Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPAR? activation to decrease diet-induced obesity.

Project description:De novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPAR?) modulates endogenous PPAR? activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPAR? transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPAR? and treatment of 3T3-L1 cells with one such ether lipid increased PPAR? transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPAR? transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPAR?-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.

| S-EPMC3467338 | biostudies-literature

Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning.

Project description:Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator-activated receptor ? coactivator 1? (PGC1?) controls BAT-mediated thermogenesis by regulating the expression of Ucp1 Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We found that adipose tissue-specific overexpression of Id1 causes age-associated and high-fat diet-induced obesity in mice. Id1 suppresses BAT thermogenesis by binding to and suppressing PGC1? transcriptional activity. In WAT, Id1 is mainly localized in the stromal vascular fraction, where the adipose progenitor/precursors reside. Lack of Id1 increases beige gene and Ucp1 expression in the WAT in response to cold exposure. Furthermore, brown-like differentiation is increased in Id1-deficient mouse embryonic fibroblasts. At the molecular level, Id1 directly interacts with and suppresses Ebf2 transcriptional activity, leading to reduced expression of Prdm16, which determines beige/brown adipocyte cell fate. Overall, the study highlights the existence of novel regulatory mechanisms between Id1/PGC1? and Id1/Ebf2 in controlling brown fat metabolism, which has significant implications in the treatment of obesity and its associated diseases, such as diabetes.

| S-EPMC5440025 | biostudies-literature

Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice.

Project description:Adiponectin is an adipocyte-derived hormone that plays an important role in energy homeostasis. The main objective of this study was to investigate whether or not adiponectin regulates brown adipose tissue (BAT) activation and thermogenesis.Core body temperatures (CBTs) of genetic mouse models were monitored at room temperature and during cold exposure. Cultured brown adipocytes and viral vector-mediated gene transduction were used to study the regulatory effects of adiponectin on Ucp1 gene expression and the underlying mechanisms.The CBTs of adiponectin knockout mice (Adipoq(-/-)) were significantly higher than those of wild type (WT) mice both at room temperature and during the cold (4°C) challenge. Conversely, reconstitution of adiponectin in Adipoq(-/-) mice significantly blunted ? adrenergic receptor agonist-induced thermogenesis of interscapular BAT. After 10 days of intermittent cold exposure, Adipoq(-/-) mice exhibited higher UCP1 expression and more brown-like structure in inguinal fat than WT mice. Paradoxically, we found that the anti-thermogenic effect of adiponectin requires neither AdipoR1 nor AdipoR2, two well-known adiponectin receptors. In sharp contrast to the anti-thermogenic effects of adiponectin, AdipoR1 and especially AdipoR2 promote BAT activation. Mechanistically, adiponectin was found to inhibit Ucp1 gene expression by suppressing ?3-adrenergic receptor expression in brown adipocytes.This study demonstrates that adiponectin suppresses thermogenesis, which is likely to be a mechanism whereby adiponectin reduces energy expenditure.

| S-EPMC4077285 | biostudies-literature

NT-PGC-1α activation attenuates high-fat diet-induced obesity by enhancing brown fat thermogenesis and adipose tissue oxidative metabolism.

Project description:The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and its splice variant N terminal (NT)-PGC-1α regulate adaptive thermogenesis by transcriptional induction of thermogenic and mitochondrial genes involved in energy metabolism. We previously reported that full-length PGC-1α (FL-PGC-1α) is dispensable for cold-induced nonshivering thermogenesis in FL-PGC-1α(-/-) mice, since a slightly shorter but functionally equivalent form of NT-PGC-1α (NT-PGC-1α(254)) fully compensates for the loss of FL-PGC-1α in brown and white adipose tissue. In the current study, we challenged FL-PGC-1α(-/-) mice with a high-fat diet (HFD) to investigate the effects of diet-induced thermogenesis on HFD-induced obesity. Despite a large decrease in locomotor activity, FL-PGC-1α(-/-) mice exhibited the surprising ability to attenuate HFD-induced obesity. Reduced fat mass in FL-PGC-1α(-/-) mice was closely associated with an increase in body temperature, energy expenditure, and whole-body fatty acid oxidation (FAO). Mechanistically, FL-PGC-1α(-/-) brown adipose tissue had an increased capacity to oxidize fatty acids and dissipate energy as heat, in accordance with upregulation of thermogenic genes UCP1 and DIO2. Furthermore, augmented expression of FAO and lipolytic genes in FL-PGC-1α(-/-) white adipose tissue was highly correlated with decreased fat storage in adipose tissue. Collectively, our data highlight a protective effect of NT-PGC-1α on diet-induced obesity by enhancing diet-induced thermogenesis and FAO.

| S-EPMC4207386 | biostudies-literature

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