Chronic North American Ginseng Administration Alters Metabolic

Variables in the Rat

Megan Migchels Supervisor: Dr. J. Ciriello2011/01/24

Overview

Background• Obesity • Obstructive Sleep Apnea• Ginseng

Hypothesis Model Preliminary Data Future experiments Questions

The Obesity Epidemic

• ~ 61% of Canadians are overweight

• This increases the risk of • Cardiovascular disease• Hypertension• Cancer• Diabetes

• Arguably leading cause of preventable death

Leptin

Secreted by adipocytes into the

bloodstream Acts on receptors in the hypothalamus

• Signals satiety• Increases energy expenditure through sympathetic activation

Initially thought to be an adipocyte signal that

functioned to prevent obesity• Leptin deficiency results in obesity• Leptin resistance in obesity

• ** Considered to play an important role in the development of hypertension in obesity**

Sleep Apnea (Intermittent Hypoxia)

Sleep Apnea is a serious disorder that occurs when a person's breathing is interrupted (stopped) during sleep.

Apnea is Greek for “without breath”. People with untreated sleep apnea stop breathing

repeatedly during their sleep, sometimes hundreds of times.

Holding your breath leads to decreased blood oxygen levels (hypoxia), which has serious consequences on the body.

Obstructive Sleep Apnea (OSA) • OSA- intermittent, cyclical cessations or

reductions of airflow because of an obstructed airway

• Prevalence of OSA is expected to rise in the coming years in response to the current obesity epidemic

Metabolic Syndrome

Ginseng

Ginseng has been used for centuries as a medicinal herb to replenish energy, reduce susceptibility to illness and promote health

Panax ginseng- Asian ginseng Panax quinquefolius- North American ginseng

Most researched herb in the world• Approximately 5% of the population of

Western countries consume ginseng

• Ginsenosides- active ingredient • The two types of ginseng differ in chemical

composition and have specific biological effects

• Previous studies: Asian Ginseng• Suggested to have anti-obesity effects, to decrease

plasma triglyceride and leptin levels (Lee, 2010)• Suggested to be anti-hypertensive (Yanai, 2006)• Improves the metabolic syndrome (Yun, 2007)

• However, little is known about the effects of

North American ginseng on cardiovascular

disease and obesity

• North American Ginseng contains 3-5x greater ginsenoside content than Asian Ginseng.

• North American Ginseng contains greater levels of ginsenoside Rb1, a phytoestrogen which has been seen to have hypotensive effects.

• North American Ginseng contains greater levels of ginsenoside Re which has vasodilatory and antihyperlipidemic properties.

Obstructive Sleep ApneaSympathetic ActivityRenin-AngiotensinOxidative Stress

Insulin ResistanceHypoxemia

Vascular Inflammation

ObesityInsulin Resistance

Vascular InflammationOxidative Stress

Endothelial DysfunctionSympathetic ActivityRenin-Angiotensin

Obstructive Sleep Apnea Increases the Risk of Cardiovascular Disease

Mechanical Obstruction of Airway

Risk Factors

Dr. John Ciriello, BSc, MSc, PhDProfessor of Physiology, Pharmacology and NeuroscienceSchulich School of Medicine and DentistryUniversity of Western Ontario – 2009.

Cardiovascular Disease(Risk Factors)Hypertension

StrokeIschemic Heart DiseaseCardiac Arrhythmias

Atherosclerosis

Patients with essential hypertension exhibit augmented increases in sympathetic nerve activity to hypoxia

Obese patients exhibit augmented increases in sympathetic nerve activityGinseng? Ginseng?

Ginseng?

Cardiovascular disease is a growing concern in our society • Hypertension• Obesity• Obstructive Sleep Apnea

Rationale

Overall Objective: • Investigate the effects of NAG treatment on the

metabolic and arterial pressure effects induced by chronic intermittent hypoxia (CIH) in normal and obese rats.

Hypothesis 1 (current ongoing study):

Chronic ingestion of NAG will reduce circulating levels of leptin• This reduction in leptin will ameliorate the effects of

obesity and CIH on the development of hypertension, dislipidemia, and insulin resistance in the obese rat.

Sprague Dawley normotensive rats on a standard rat chow diet

Sprague Dawley rats on a high-fat diet (45kcal fat)

Normal and obese Sprague Dawley rats exposed to Chronic Intermittent Hypoxia (60s episode at 6-7% O2 followed by 2 mins room air 20.5% O2.)

Ethanol extract of Panax quinquefolius by gavage: 0 or 250mg/kg

in 0.9%saline every day before 1900 hrs

for 28 days

Model

Weekly measurements of• Blood pressure and heart rate by indirect tail cuff

method (CODA system)• Body weight• Metabolism: Food/water intake, Urinary

output, Urine Na+, K+

After sacrifice• Brainstem effects: Fos/Fra to detect central areas

activated in response to administration of ginseng• Circulating levels of leptin, insulin• Obesity study:

Lipid profileso Triglycerideso Cholesterol

Retroperitoneal fat pad Epididymal fat pad

Cumulative Weight Change

0 1 2 3 40

50

100

150

200

ND Control ND GinsengHFD ControlHFD Ginseng

Week

Cu

mu

lati

ve

Weig

ht

Gain

(g

)

*

**

0 1 2 3 4275

325

375

425

475

525

575

ND ControlND GinsengHF ControlHF Ginseng

Week

Bod

y W

eig

ht

(g)

*

(n= 5)

(n= 5)(n= 5)

(n= 5)

Food Intake

(n= 4-5)(n= 4-5)

* * * ** * * *

Retroperitoneal Fat Pad*

*

**

Epididymal Fat Pad*

*

*

*

Plasma Leptin Concentration

*

*

*

*

*

*

Plasma Triglycerides

Total plasma cholesterol

Blood Glucose

Diet

**

Plasma Insulin

Insulin Resistance

Mean Arterial Pressure

Normal Diet

Normal Diet

High Fat Diet

Heart RateNormal Diet

High Fat Diet

Normal Diet

No statistical differences were seen in• Heart weight• Kidney weight• Hematocrit• Water intake• Urine output

Ongoing Studies

Increasing ‘n’ values• Normal/High fat diets

Analyze brain sections processed for cfos/Fra immunohistochemistry

Western blot and qPCR for long form of leptin receptor in brainstem/hypothalamus

Chronic Intermittent Hypoxia• Model of Obstructive Sleep Apnea

Questions