bioRxiv ScienceSearch

Biology subjects

Foright, R. M.

Publications and source records attributed to Foright, R. M..

2 recordsLinked to original sources

A high fat anti-inflammatory diet improves widespread allodynia despite worsening metabolic outcomes in adult mice exposed to neonatal maternal separation

Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether an anti-inflammatory diet (AID) containing a combination of key anti-inflammatory compounds, at clinically relevant doses, improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS). Our results demonstrate a benefit of the AID on pain-like behaviors, despite the diet being high in fat, which led to increased caloric intake, adiposity, and weight gain. The AID specifically increased measures of metabolic syndrome and inflammation in female mice, compared to an isocaloric, macronutrient-matched diet lacking the anti-inflammatory compounds. Male mice, especially those exposed to NMS, were equally susceptible to both diets worsening metabolic measures. This work highlights important sexual dimorphic outcomes related to early life stress exposure and dietary interventions, as well as a potential disconnect between improvements in pain-like behaviors and metabolic measures.

physiology

Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

Breast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use associated with larger breast adipocyte diameter only in women with a BMI >30 kg/m2. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in single-cell RNA sequencing of mesenchymal stem cells from adipose tissue, endocrine therapies induced adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. Metformin or pioglitazone, glucose lowering drugs used to treat diabetes, prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies act via ER to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

physiology