NURS presentation Daniel Svedberg 071316

Role of Brown Adipose Tissue Innervation in Resistance to Stress-Induced Obesity at Thermoneutrality

Daniel Svedberg, Dr. Maria Razzoli, Dr. Alessandro Bartolomucci

Department of PhysiologyUniversity of Minnesota-Twin Cities


• Human obesity is a prevalent1 and profound healthcare problem2

• Mood disorders and obesity are strongly associated in humans3

• For these experiments, we use Chronic Subordination Stress (CSS) to study the relationship between psychosocial stress and obesity in mice4

The Chronic Subordination Stress Protocol:

6) the chronic subordination stress protocol typically lasts 4 weeks

1) Ogden, Cynthia L et al. “Prevalence of Childhood and Adult Obesity in the United States, 2011-2012.” JAMA : the journal of the American Medical Association 311.8 (2014): 806–14. Web. 9 July 2014.

2) Billington, Charles J., et al. "Overweight, obesity, and health risk." Archives of Internal Medicine160.7 (2000): 898-904.

3) McElroy, Susan L., et al. "Are mood disorders and obesity related? A review for the mental health professional." The Journal of clinical psychiatry65.5 (2004): 634-651.4) Sanghez, Valentina et al. “Psychosocial Stress Induces Hyperphagia and Exacerbates Diet-Induced Insulin Resistance and the

Manifestations of the Metabolic Syndrome.” Psychoneuroendocrinology 38.12 (2013): 2933–42. Web. 2 Dec. 2015.

• Brown adipose tissue (BAT) is an adipose organ that uptakes circulating glucose and triglycerides, and then uncouples mitochondrial ATP synthesis to produce heat1

• BAT activation is negatively associated with obesity in humans2, and directly prevents obesity in mice3

• Activating BAT a target for medical interventions combating obesity and metabolic disorders 1

• Experiments in mice show that CSS affects BAT function, which has a synergistic effect on obesity4

van Marken Lichtenbelt WD et al. N Engl J Med 2009;360:1500-1508.Adapted from: Harms, Matthew, and Patrick Seale. Nature medicine 19.10 (2013): 1252-1263.

Cantó, Carles, and Pablo M. Garcia‐Roves. Current protocols in mouse biology (2014): 135-153.

1) Harms, Matthew, and Patrick Seale. “Brown and Beige Fat: Development, Function and Therapeutic Potential.” Nature medicine 19.10 (2013): 1252–63. Web. 11 July 2014.

3) Feldmann, Helena M et al. “UCP1 Ablation Induces Obesity and Abolishes Diet-Induced Thermogenesis in Mice Exempt from Thermal Stress by Living at Thermoneutrality.” Cell metabolism 9.2 (2009): 203–9. Web. 2 Dec. 2015.

2) Aaron M. Cypess, M.D., Ph.D., M.M.Sc., Sanaz Lehman, M.B., B.S., Gethin Williams, M.B., B.S., Ph.D., Ilan Tal, Ph.D., Dean Rodman, M.D., Allison B. Goldfine, M.D., Frank C. Kuo, M.D., Ph.D., Edwin L. Palmer, M.D., Yu-Hua Tseng, Ph.D., Alessandro Doria, M., M.D. “Identification and Importance of Brown Adipose Tissue in Adult Humans.” New England Journal of Medicine 360 (2009): 1509–1517. Web. 2 Dec. 2015.


4) Razzoli, Maria, et al. "Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis."Molecular metabolism 5.1 (2016): 19-33.

• Thermoneutrality: 30°C• A condition of low adaptive thermogenesis: BAT becomes

atrophied and dysfunctional • A closer model of BAT function in humans: through

clothing/temperature control, humans live at thermoneutrality

• Subjecting mice (acclimatized to thermoneutrality) to stress reverses the typical vulnerability to obesity caused by stress1

• mediated by increased brown adipose tissue activation from an initially low level of activation


Razzoli, Maria, et al. "Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis." Molecular metabolism 5.1 (2016): 19-33.

TyrosineHydroxylase

Fibers

Control Stress

UCP1

• Chronic subordination stress, in mice acclimatized to thermoneutrality, normalizes BAT morphology

• Increased expression of UCP1• Increased innervation by

sympathetic nerve fibers



• In this model, the sympathetic nerves innervating the BAT are responsible for mediating the recruitment of BAT in response to stress, thereby preventing obesity

• In order to test this, we must isolate the influence of the sympathetic nerves



At thermoneutrality:

Experimental Design

Experimental Groups Sham Surgery Denervation Control Sham-Control Denervation-ControlStress Sham-Stress Denervation-Stress

Denervation of BAT:

The Chronic Subordination Stress Protocol:

In mice acclimatized to thermoneutrality (30°C), we denervated the BAT and subjected experimental mice to chronic subordination stress

Vaughan, Cheryl H., et al. Methods in enzymology 537 (2014): 199.

0 5 10 15 20 25 30 35 40

Body Weight

Food Intake

Body Weight

Food Intake

Timeline of Experiment

Days

Weight change:

Baseli

ne

Stress period begins immediately after baseline measurement

N=9 for all groups. Error bars shown are ±SEM

***

High-fat diet after first week of stress

denerv

Food Intake:


Baseli

ne

Stress period begins immediately after baseline measurement

High-fat diet after first week of stress

denerv

Body Composition:


**

Conclusions• At thermoneutrality, surgical

denervation of the BAT followed by CSS leads to increased weight gain and prevents CSS-induced decrease in fat mass.

• It is likely that this is due to an impairment in adipose tissue browning, which would otherwise be mediated by the sympathetic nerves

Future Directions• Quantification of UCP1

protein and expression of key thermogenesis, adipogenesis, and mitochondrial function genes

• Immunohistochemical staining of BAT to characterize sympathetic innervation and VNUT expression

Bartolomucci Lab/Acknowledgements

Dr. Alessandro Bartolomucci (Principal Investigator)Maria Razzoli. PhDRuijun Han, PhDBhavani Shankar Sahu, PhDJessica PatricelliDaniel SvedbergFormer:Cheryl Cero (NIDDK) Valentina Sanghez (UCLA) Kewir Dufe (Univ Calgary)Raffaello Verardi (NICHD)

The Winston and Maxine Wallin Neuroscience Discovery Fund

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NURS presentation Daniel Svedberg 071316