Implications of estrogen receptor alpha (ERa) with the intersection of organophosphate flame retardants and diet-induced obesity in adult mice.

Previously, organophosphate flame retardants (OPFRs) were found to produce intersecting disruptions of energy homeostasis using an adult mouse model of diet-induced obesity. Using the same mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study aimed to identify the role of estrogen receptor alpha (ERα) in OPFR-induced disruption, utilizing ERα knockout (ERαKO) mice fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, food intake patterns, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were measured. When fed HFD, no marked direct effects of OPFR were observed in mice lacking ERα, suggesting a role for ERα in generating previously reported wildtype (WT) findings. Male ERαKO mice fed LFD experienced decreased feeding efficiency and altered insulin tolerance, whereas their female counterparts displayed less fat mass and circulating ghrelin when exposed to OPFRs. These effects were not noted in the previous WT study, indicating that loss of ERα may sensitize animals fed LFD to alternate pathways of endocrine disruption by OFPRs. Collectively, these data demonstrate both direct and indirect actions of OPFRs on ERα-mediated pathways governing energy homeostasis and support a growing body of evidence urging concern for risk of human exposure.

Implications of peroxisome proliferator-activated receptor gamma (PPARY) with the intersection of organophosphate flame retardants and diet-induced obesity in adult mice.

Previously, organophosphate flame retardants (OPFRs) were demonstrated to dysregulate homeostatic parameters of energy regulation within an adult mouse model of diet-induced obesity. Using the same OPFR mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study examined the role of peroxisome proliferator-activated receptor gamma (PPARγ) in OPFR-induced disruption by utilizing mice with brain-specific deletion of PPARγ (PPARγKO) fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, feeding behavior, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were recorded. When fed HFD, the effects of OPFR on body weight and feeding behavior observed in the previous wild-type (WT) study were absent in mice lacking neuronal PPARγ. This posits PPARγ as an important target for eliciting OPFR disruption in a diet-induced obesity model. Interestingly, female PPARγKO mice, but not males, experienced many novel OPFR effects not noted in WT mice, including decreased fat mass, altered feeding behavior and efficiency, improved insulin sensitivity, elevated plasma ghrelin and hypothalamic expression of its receptor. Taken together, these data suggest both direct roles for PPARγ in OPFR disruption of obese mice and indirect sensitization of pathways alternative to PPARγ when neuronal expression is deleted.

Insulin actions on hypothalamic glucose-sensing neurones.

Subsequent to the discovery of insulin 100 years ago, great strides have been made in understanding its function, especially in the brain. It is now clear that insulin is a critical regulator of the neuronal circuitry controlling energy balance and glucose homeostasis. This review focuses on the effects of insulin and diabetes on the activity and glucose sensitivity of hypothalamic glucose-sensing neurones. We highlight the role of electrophysiological data in understanding how insulin regulates glucose-sensing neurones. A brief introduction describing the benefits and limitations of the major electrophysiological techniques used to investigate glucose-sensing neurones is provided. The mechanisms by which hypothalamic neurones sense glucose are discussed with an emphasis on those glucose-sensing neurones already shown to be modulated by insulin. Next, the literature pertaining to how insulin alters the activity and glucose sensitivity of these hypothalamic glucose-sensing neurones is described. In addition, the effects of impaired insulin signalling during diabetes and the ramifications of insulin-induced hypoglycaemia on hypothalamic glucose-sensing neurones are covered. To the extent that it is known, we present hypotheses concerning the mechanisms underlying the effects of these insulin-related pathologies. To conclude, electrophysiological data from the hippocampus are evaluated aiming to provide clues regarding how insulin might influence neuronal plasticity in glucose-sensing neurones. Although much has been accomplished subsequent to the discovery of insulin, the work described in our review suggests that the regulation of central glucose sensing by this hormone is both important and understudied.

Organophosphate Flame Retardants Excite Arcuate Melanocortin Circuitry and Increase Neuronal Sensitivity to Ghrelin in Adult Mice.

Organophosphate flame retardants (OPFRs) are a class of chemicals that have become near ubiquitous in the modern environment. While OPFRs provide valuable protection against flammability of household items, they are increasingly implicated as an endocrine disrupting chemical (EDC). We previously reported that exposure to a mixture of OPFRs causes sex-dependent disruptions of energy homeostasis through alterations in ingestive behavior and activity in adult mice. Because feeding behavior and energy expenditure are largely coordinated by the hypothalamus, we hypothesized that OPFR disruption of energy homeostasis may occur through EDC action on melanocortin circuitry within the arcuate nucleus. To this end, we exposed male and female transgenic mice expressing green fluorescent protein in either neuropeptide Y (NPY) or proopiomelanocortin (POMC) neurons to a common mixture of OPFRs (triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate; each 1 mg/kg bodyweight/day) for 4 weeks. We then electrophysiologically examined neuronal properties using whole-cell patch clamp technique. OPFR exposure depolarized the resting membrane of NPY neurons and dampened a hyperpolarizing K+ current known as the M-current within the same neurons from female mice. These neurons were further demonstrated to have increased sensitivity to ghrelin excitation, which more potently reduced the M-current in OPFR-exposed females. POMC neurons from female mice exhibited elevated baseline excitability and are indicated in receiving greater excitatory synaptic input when exposed to OPFRs. Together, these data support a sex-selective effect of OPFRs to increase neuronal output from the melanocortin circuitry governing feeding behavior and energy expenditure, and give reason for further examination of OPFR impact on human health.

The interactions of diet-induced obesity and organophosphate flame retardant exposure on energy homeostasis in adult male and female mice.

Previously, sex-dependent alterations in energy homeostasis were reported in adult mice fed a standard chow attributed to exposure to a mixture of organophosphate flame retardants (OPFRs) via estrogen receptors (ERα). In this study, adult male and female mice (C57BL/6J; Taconic) were treated with the same mixture of OPFRs (1 mg/kg each of tricresyl phosphate (TCP), triphenyl phosphate (TPP), and tris(1-3-dichloro-2propyl)phosphate (TDCPP)) for 7 weeks on a low-fat diet (LFD, 10% kcal fat) or a high fat (HFD, 45% kcal fat) in a diet-induced obesity model. Consistent with our previous observations, OPFRs altered weight gain in males, differentially with diet, while females remained unaffected. OPFR treatment also revealed sex-dependent perturbations in metabolic activity. During the night (approximately 0100-0400 hr), males exhibited elevated activity and oxygen consumption, while in females these parameters were decreased, irrespective of diet. OPFR disrupted feeding behavior and abolished diurnal water intake patterns in females while increasing nighttime fluid consumption in males. Despite no marked effect of OPFRs on glucose or insulin tolerance, OPFR treatment altered circulating insulin and leptin in females and ghrelin in males. Data indicate that adult OPFR exposure might influence, and perhaps exacerbate, the effects of diet-induced obesity in adult mice by altering activity, ingestive behavior, and metabolism.