Beta 3 Adrenergic Receptor Activation Rescues Metabolic Dysfunction in Female Estrogen Receptor Alpha-Null Mice

Metabolic disease risk escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through estrogen receptor alpha (ERα), which is highly expressed in brown and white adipose tissue (BAT and WAT).Objective: Test the hypothesis that uncoupling protein (UCP1) activation mitigates metabolic dysfunction caused by loss of signaling through ERα.Methods: At 8 weeks of age, female ERα knock out (KO) and wild-type mice were housed at 28°C and fed a Western-style high-fat, high sucrose diet (HFD) or a normal low-fat chow diet (NC) for 10 weeks. During the final 2 weeks, they received daily injections of CL 316,256 (CL), a selective β3 adrenergic agonist, or vehicle control (CTRL), creating eight groups: WT-CTRL, WT-CL, KO-CTRL, and KO-CL on HFD or NC; n = 4–10/group.Results: ERαKO demonstrated exacerbated HFD-induced adiposity gain (P < 0.001) and insulin resistance (P = 0.006). CL treatment improved insulin sensitivity (P < 0.05) and normalized ERαKO-induced adiposity increase (P < 0.05). In both genotypes, CL increased resting energy expenditure (P < 0.05) and induced WAT beiging indicated by increased UCP1 protein in both perigonadal (PGAT) and subcutaneous (SQAT) depots. These effects were attenuated under HFD conditions (P < 0.05). In KO, CL reduced HFD energy consumption compared to CTRL (P < 0.05). Remarkably, CL increased WAT ERβ protein levels of both WT and KO (P < 0.001), revealing CL-mediated changes in estrogen signaling may have protective metabolic effects.Conclusion: CL completely restored metabolic dysfunction in ERαKO mice. Thus, UCP1 may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling

Differential effects of increasing physical activity and reducing energy intake on cardiometabolic and energetic parameters in obesity-prone juvenile rats

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Although the rise in adolescent obesity plateaued from 2003 to 2012, health implications associated with excess adiposity in the adolescent years remain problematic. As such, we utilized an obesity-prone (OP) rat model to investigate how physical activity affects whole body energetics and metabolism as well as adipose tissue-specific changes during the juvenile period. Male OP rats were obtained at 4 wks of age and randomized into one of the following three groups (n=10/group): 1) high-fat diet (HFD), sedentary (Sed), 2) HFD exercise (Ex), or 3) HFD weight-matched (WM). Animals were placed in indirect calorimetry chambers at 11 wks of age and glucose tolerance tests were conducted at 12 wks. Animals were sacrificed from 16- 18 wks of age. BW gain was significantly attenuated with WM equal to the Ex group for the duration of the study (Sed 569[plus or minus]12.89g, Ex 467[plus or minus]19.80g, WM 476[plus or minus]3.38g; p less than 0.05). Dark cycle spontaneous physical activity (SPA) was significantly increased in the Ex group in comparison to Sed and WM groups. Using the Matsuda index (MI), Ex significantly improved insulin sensitivity compared to the WM and Sed group (Sed: 2.18[plus or minus]0.33MI, Ex: 5.13[plus or minus]0.02MI, WM: 2.25[plus or minus]0.27MI, p less than 0.05). Both Ex and WM groups experienced reductions in pro-inflammatory markers with concomitant increases in anti-inflammatory genes across multiple adipose tissue depots. We found that the two interventions were almost equivocal in terms of improvements in body composition and reducing adipose tissue inflammation. We also found that voluntary exercise increased SPA while, both interventions increased total energy expenditure

Knockdown of Esr1 from DRD1-Rich Brain Regions Affects Adipose Tissue Metabolism: Potential Crosstalk between Nucleus Accumbens and Adipose Tissue

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2’s effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc

Physical Activity Differentially Affects the Cecal Microbiota of Ovariectomized Female Rats Selectively Bred for High and Low Aerobic Capacity.

The gut microbiota is considered a relevant factor in obesity and associated metabolic diseases, for which postmenopausal women are particularly at risk. Increasing physical activity has been recognized as an efficacious approach to prevent or treat obesity, yet the impact of physical activity on the microbiota remains under-investigated. We examined the impacts of voluntary exercise on host metabolism and gut microbiota in ovariectomized (OVX) high capacity (HCR) and low capacity running (LCR) rats. HCR and LCR rats (age = 27 wk) were OVX and fed a high-fat diet (45% kcal fat) ad libitum and housed in cages equipped with (exercise, EX) or without (sedentary, SED) running wheels for 11 wk (n = 7-8/group). We hypothesized that increased physical activity would hinder weight gain, increase metabolic health and shift the microbiota of LCR rats, resulting in populations more similar to that of HCR rats. Animals were compared for characteristic metabolic parameters including body composition, lipid profile and energy expenditure; whereas cecal digesta were collected for DNA extraction. 16S rRNA gene-based amplicon Illumina MiSeq sequencing was performed, followed by analysis using QIIME 1.8.0 to assess cecal microbiota. Voluntary exercise decreased body and fat mass, and normalized fasting NEFA concentrations of LCR rats, despite only running one-third the distance of HCR rats. Exercise, however, increased food intake, weight gain and fat mass of HCR rats. Exercise clustered the gut microbial community of LCR rats, which separated them from the other groups. Assessments of specific taxa revealed significant (p<0.05) line by exercise interactions including shifts in the abundances of Firmicutes, Proteobacteria, and Cyanobacteria. Relative abundance of Christensenellaceae family was higher (p = 0.026) in HCR than LCR rats, and positively correlated (p<0.05) with food intake, body weight and running distance. These findings demonstrate that exercise differentially impacts host metabolism and gut microbial communities of female HCR and LCR rats without ovarian function

White Adipose Tissue Depots Respond to Chronic Beta-3 Adrenergic Receptor Activation in a Sexually Dimorphic and Depot Divergent Manner

Beta-3 adrenergic receptor activation via exercise or CL316,243 (CL) induces white adipose tissue (WAT) browning, improves glucose tolerance, and reduces visceral adiposity. Our aim was to determine if sex or adipose tissue depot differences exist in response to CL. Daily CL injections were administered to diet-induced obese male and female mice for two weeks, creating four groups: male control, male CL, female control, and female CL. These groups were compared to determine the main and interaction effects of sex (S), CL treatment (T), and WAT depot (D). Glucose tolerance, body composition, and energy intake and expenditure were assessed, along with perigonadal (PGAT) and subcutaneous (SQAT) WAT gene and protein expression. CL consistently improved glucose tolerance and body composition. Female PGAT had greater protein expression of the mitochondrial uncoupling protein 1 (UCP1), while SQAT (S, p &lt; 0.001) was more responsive to CL in increasing UCP1 (S&times;T, p = 0.011) and the mitochondrial biogenesis induction protein, PPAR&gamma; coactivator 1&alpha; (PGC1&alpha;) (S&times;T, p = 0.026). Females also displayed greater mitochondrial OXPHOS (S, p &lt; 0.05) and adiponectin protein content (S, p &lt; 0.05). On the other hand, male SQAT was more responsive to CL in increasing protein levels of PGC1&alpha; (S&times;T, p = 0.046) and adiponectin (S, p &lt; 0.05). In both depots and in both sexes, CL significantly increased estrogen receptor beta (ER&beta;) and glucose-related protein 75 (GRP75) protein content (T, p &lt; 0.05). Thus, CL improves systemic and adipose tissue-specific metabolism in both sexes; however, sex differences exist in the WAT-specific effects of CL. Furthermore, across sexes and depots, CL affects estrogen signaling by upregulating ER&beta;

Retention of sedentary obese visceral white adipose tissue phenotype with intermittent physical activity despite reduced adiposity

Regular physical activity is effective in reducing visceral white adipose tissue (AT) inflammation and oxidative stress, and these changes are commonly associated with reduced adiposity. However, the impact of multiple periods of physical activity, intercalated by periods of inactivity, i.e., intermittent physical activity, on markers of AT inflammation and oxidative stress is unknown. In the present study, 5-wk-old male C57BL/6 mice were randomized into three groups (n = 10/group): sedentary, regular physical activity, and intermittent physical activity, for 24 wk. All animals were singly housed and fed a diet containing 45% kcal from fat. Regularly active mice had access to voluntary running wheels throughout the study period, whereas intermittently active mice had access to running wheels for 3-wk intervals (i.e., 3 wk on/3 wk off) throughout the study. At death, regular and intermittent physical activity was associated with similar reductions in visceral AT mass (approximately −24%, P < 0.05) relative to sedentary. However, regularly, but not intermittently, active mice exhibited decreased expression of visceral AT genes related to inflammation (e.g., monocyte chemoattractant protein 1), immune cell infiltration (e.g., CD68, CD11c, F4/80, CD11b/CD18), oxidative stress (e.g., p47 phagocyte oxidase), and endoplasmic reticulum stress (e.g., CCAAT enhancer-binding protein homologous protein; all P < 0.05). Furthermore, regular, but not intermittent, physical activity was associated with a trend toward improvement in glucose tolerance (P = 0.059). Collectively, these findings suggest that intermittent physical activity over a prolonged period of time may lead to a reduction in adiposity but with retention of a sedentary obese white AT and metabolic phenotype

Relative Microbial Abundance and Food Intakes Correlation.

<p>Correlations between the relative abundance of the bacterial communities (OTU) and food intake at wk11 of dietary and exercise interventions. Pearson correlation coefficients (r) are shown for each taxon: (A) Christensenellaceae, (B) Porphyromonadaceae, (C) Clostridiaceae, (D) Peptococcaceae, and (E) Desulfovibrionaceae, with the associated <i>p</i> values.</p

Body weight, food intake and daily wheel running distance¹.

<p>¹n = 7-8/group, values are means ± SEM.</p><p>²Body weight, food intake and running distance were measured weekly. Feed efficiency was calculated by dividing amount of energy consumed by each animal by the BW gain. These data represent the mean throughout the 11-wk period.</p><p>³BW = body weight; HCR = high capacity runner rats; LCR = low capacity runner rats; EX = voluntary exercise; SED = sedentary.</p><p>⁴Energy expenditure was measured using indirect calorimetry over a 3-d period at 36 wk of age.</p><p>Body weight, food intake and daily wheel running distance<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136150#t001fn001" target="_blank">¹</a>.</p