Erythropoietin Non-hematopoietic Tissue Response and Regulation of Metabolism During Diet Induced Obesity

Erythropoietin (EPO) receptor (EPOR) determines EPO response. High level EPOR on erythroid progenitor cells gives rise to EPO regulated production of red blood cells. Animal models provide evidence for EPO activity in non-hematopoietic tissue mediated by EPOR expression. Beyond erythropoiesis, EPO activity includes neuroprotection in brain ischemia and trauma, endothelial nitric oxide production and cardioprotection, skeletal muscle wound healing, and context dependent bone remodeling affecting bone repair or bone loss. This review highlights examples of EPO protective activity in select non-hematopoietic tissue with emphasis on metabolic response mediated by EPOR expression in fat and brain and sex-specific regulation of fat mass and inflammation associated with diet induced obesity. Endogenous EPO maintains glucose and insulin tolerance and protects against fat mass accumulation and inflammation. Accompanying the increase in erythropoiesis with EPO treatment is improved glucose tolerance and insulin response. During high fat diet feeding, EPO also decreases fat mass accumulation in male mice. The increased white adipose tissue inflammation and macrophage infiltration associated with diet induced obesity are also reduced with EPO treatment with a shift toward an anti-inflammatory state and decreased inflammatory cytokine production. In female mice the protective effect of estrogen against obesity supersedes EPO regulation of fat mass and inflammation, and requires estrogen receptor alpha activity. In brain, EPOR expression in the hypothalamus localizes to proopiomelanocortin neurons in the arcuate nucleus that promotes a lean phenotype. EPO stimulation of proopiomelanocortin neurons increases STAT3 signaling and production of proopiomelanocortin. Cerebral EPO contributes to metabolic response, and elevated brain EPO reduces fat mass and hypothalamus inflammation during diet induced obesity in male mice without affecting EPO stimulated erythropoiesis. Ovariectomy abrogates the sex-specific metabolic response of brain EPO. The sex-dimorphic EPO metabolic response associated with fat mass accumulation and inflammation during diet induced obesity provide evidence for crosstalk between estrogen and EPO in their anti-obesity potential in female mice mediated in part via tissue specific response in brain and white adipose tissue. Endogenous and exogenous EPO response in non-hematopoietic tissue demonstrated in animal models suggests additional activity by which EPO treatment may affect human health beyond increased erythropoiesis.

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Metabolic Burden of Erythropoietin Stimulated Erythropoiesis in Mice

Blood ◽

10.1182/blood.v128.22.2421.2421 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2421-2421

Author(s):

Constance Tom Noguchi ◽

Heather Marie Rogers

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Male Mice ◽

Wild Type ◽

Hematopoietic Tissue ◽

High Fat ◽

Epor Expression

Erythropoietin (EPO) promotes erythroid differentiation and increases glucose uptake in erythroid progenitor cells in culture. The metabolic burden associated with EPO treatment in adult mice is suggested by a decrease in body weight concomitant with increased hematocrit. Wild type male mice (C57Bl/6, age 8 months) treated with EPO showed the expected increase in hematocrit accompanied by a fall in blood glucose level and a decrease in body weight and fat mass. However, the decrease in body weight is even more evident in obese mice on a high fat diet and has also been linked to non-hematopoietic response, particularly with EPO receptor (EpoR) expression in white adipose tissue. We examined the metabolic burden of EPO treatment (3000U/kg for 3 weeks) in young, lean male mice (3 months) placed on high fat diet at the time of EPO administration. The increase in hematocrit was accompanied by decreased blood glucose level and improved glucose tolerance. However, no difference in body weight was observed between mice treated with EPO and the saline treated group, suggesting that the EPO stimulated decrease in body weight is evident primarily in older animals with greater fat mass. To determine the contribution of EpoR expression in non-hematopoietic tissue to the metabolic EPO response, young male mice with EpoR restricted to erythroid tissue (TgEpoR) were placed on high fat diet and treated with EPO. The expected increased hematocrit was also accompanied by decreased blood glucose level and improved glucose tolerance, and no change in body weight between EPO and saline treatment. The similar responses observed in young wild type and TgEpoR mice suggest that the EPO stimulated increase in glucose metabolism is associated with increased erythropoiesis rather than a direct EPO response in non-hematopoietic tissue. TgEpoR mice exhibit an age dependent increase in fat mass even greater than that observed in wild type mice, and by 8 months TgEpoR mice are obese, glucose intolerant and insulin resistant compared with wild type mice. At 8 months, TgEpoR mice treated with EPO show the increase in hematocrit and, despite the increase in fat mass, there is only a minimal decrease in body weight compared with wild type mice. These data provide evidence that in addition to the age dependent association of EPO stimulated decrease in body weight and fat mass, this decrease in body weight is due largely to EPO response related to EpoR expression in non-hematopoietic tissue. Interestingly, young male mice with targeted deletion of EpoR in adipose tissue placed on a high fat diet and treated with EPO show the increase in hematocrit and improvement in glucose tolerance, and at 8 months, the increase in hematocrit with EPO treatment is accompanied by minimal change in body weight. The similar metabolic response of these mice with targeted deletion of EpoR in adipose tissue to TgEpoR mice indicate the contribution of EpoR expression in adipose tissue to the loss of body weight and fat mass. Therefore, the metabolic burden associated with EPO stimulated erythropoiesis appears to be reflected in improved glucose metabolism and glucose tolerance with minimal or no effect on body weight, is evident in young, lean mice, and is independent of EpoR expression in non-hematopoietic tissue. In older mice, non-hematopoietic metabolic EPO response is more readily apparent as reflected in loss of body weight/fat mass, which overshadows the erythropoietic metabolic response. In combination, the metabolic response to EPO treatment results from EPO stimulated increased erythropoiesis, improved glucose metabolism and glucose tolerance, and an age dependent decrease in body weight and fat mass associated with EpoR expression in non-hematopoietic tissue, particularly in white adipose tissue. Disclosures No relevant conflicts of interest to declare.

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Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue

10.2337/figshare.13681663 ◽

2021 ◽

Author(s):

Pasquale Nigro ◽

Roeland J. W. Middelbeek ◽

Christiano R. R. Alves ◽

Susana Rovira–Llopis ◽

Krithika Ramachandran ◽

...

Keyword(s):

Adipose Tissue ◽

Exercise Training ◽

White Adipose Tissue ◽

Metabolic Response ◽

Wheel Running ◽

Secretory Protein ◽

Acid Uptake ◽

Male Mice ◽

Female Mice ◽

Response To Exercise

Recent studies demonstrate that adaptations to white adipose tissue are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal white adipose tissue (iWAT) in male mice including decreasing fat mass, improving mitochondrial function, inducing beiging and stimulating the secretion of adipokines. Here, we find that despite performing more voluntary wheel running compared to males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor co-activators are upregulated in iWAT from trained male mice, and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex-specificity also occurs in the secretome profile, as we identify Cysteine Rich Secretory Protein 1(<i>Crisp1</i>) as a novel adipokine that is only secreted from male iWAT in response to exercise. <i>Crisp1</i> expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females, and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

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Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue

10.2337/figshare.13681663.v1 ◽

2021 ◽

Author(s):

Pasquale Nigro ◽

Roeland J. W. Middelbeek ◽

Christiano R. R. Alves ◽

Susana Rovira–Llopis ◽

Krithika Ramachandran ◽

...

Keyword(s):

Adipose Tissue ◽

Exercise Training ◽

White Adipose Tissue ◽

Metabolic Response ◽

Wheel Running ◽

Secretory Protein ◽

Acid Uptake ◽

Male Mice ◽

Female Mice ◽

Response To Exercise

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Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity

Diabetes ◽

10.2337/db13-0883 ◽

2014 ◽

Vol 63 (7) ◽

pp. 2415-2431 ◽

Cited By ~ 28

Author(s):

M. Alnaeeli ◽

B. M. Raaka ◽

O. Gavrilova ◽

R. Teng ◽

T. Chanturiya ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Diet Induced Obesity

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Carbonyl Reductase 1 Overexpression in Adipose Amplifies Local Glucocorticoid Action and Impairs Glucose Tolerance in Lean Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1639 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A806-A806

Author(s):

Rachel Bell ◽

Elisa Villalobos ◽

Mark Nixon ◽

Allende Miguelez-Crespo ◽

Matthew Sharp ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Fasting Glucose ◽

High Fat ◽

Male And Female ◽

Over Expression ◽

Female Mice ◽

Diet Induced Obesity

Abstract Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.

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A novel dual-targeted rosiglitazone-loaded nanoparticle for the prevention of diet-induced obesity via the browning of white adipose tissue

Journal of Controlled Release ◽

10.1016/j.jconrel.2020.10.002 ◽

2020 ◽

Author(s):

Ryu Hiradate ◽

Ikramy A. Khalil ◽

Aya Matsuda ◽

Mika Sasaki ◽

Kyoko Hida ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Diet Induced Obesity

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Changes of fat-mass and obesity-associated protein expression in the hippocampus in animal models of high-fat diet-induced obesity and D-galactose-induced aging

Laboratory Animal Research ◽

10.1186/s42826-020-00046-0 ◽

2020 ◽

Vol 36 (1) ◽

Author(s):

Min Soo Kang ◽

Woosuk Kim ◽

Tae Hyeong Kim ◽

Hyo Young Jung ◽

Hyun Jung Kwon ◽

...

Keyword(s):

Animal Models ◽

Protein Expression ◽

Fat Mass ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity

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Zinc-α2-glycoprotein promotes browning of white adipose tissue in cold-exposed male mice

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2019.110669 ◽

2020 ◽

Vol 501 ◽

pp. 110669 ◽

Cited By ~ 2

Author(s):

Guoqiang Fan ◽

Xiaobo Dang ◽

Yanfei Li ◽

Jinglong Chen ◽

Ruqian Zhao ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Male Mice

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Endocrine and Metabolic Signaling in Retroperitoneal White Adipose Tissue Remodeling during Cold Acclimation

Journal of Obesity ◽

10.1155/2013/937572 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Aleksandra Jankovic ◽

Aleksandra Korac ◽

Biljana Buzadzic ◽

Vesna Otasevic ◽

Ana Stancic ◽

...

Keyword(s):

Adipose Tissue ◽

Cold Acclimation ◽

White Adipose Tissue ◽

Protein Level ◽

Metabolic Response ◽

Expression Profiles ◽

Hypoxia Inducible Factor ◽

Metabolic Remodeling ◽

Retroperitoneal White Adipose Tissue ◽

Adipose Tissue Remodeling

The expression profiles of adiponectin, resistin, 5′-AMP-activated protein kinaseα(AMPKα), hypoxia-inducible factor-1α(HIF-1α), and key enzymes of glucose and fatty acid metabolism and oxidative phosphorylation in rat retroperitoneal white adipose tissue (RpWAT) during 45-day cold acclimation were examined. After transient suppression on day 1, adiponectin protein level increased following sustained cold exposure. In parallel, on day 1, the protein level of HIF-1αwas strongly induced and AMPKαsuppressed, while afterwards the reverse was seen. What is more, after an initial decrease on day 1, a sequential increase in pyruvate dehydrogenase, acyl-CoA dehydrogenase, cytochromecoxidase, and ATP synthase and a decrease in acetyl-CoA carboxylase (from day 3) were observed. Similar to adiponectin, protein level of resistin showed a biphasic profile: it increased after days 1, 3, and 7 and decreased below the control after 21 days of cold-acclimation. In summary, the data suggest that adiponectin and resistin are important integrators of RpWAT metabolic response and roles it plays during cold acclimation. It seems that AMPKαmediate adiponectin effects on metabolic remodeling RpWAT during cold acclimation.

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