Obesity Management: Pivotal

Components of Innovative
Therapeutics

Stephen Holt MD, LLD (Hon.) DSc, ChB., PhD, DNM,

FRCP (C), MRCP (UK), FACP, FACG, FACN, FACAM,
OSJ

Distinguished Professor of Medicine (Emeritus)

Scientific Advisor, Natural Clinician LLC
MULTIPRONGED OBESITY TREATMENT

• Calorie restriction (high/low diet),

exercise, behaviour modification,
adjuncts (supplements or drugs)
• In many individuals, overweight status
goes hand in hand with Metabolic
Syndrome X, an inflammatory status
(OBESITIS), body toxicity and genetics
• Managing obesity and related disease
in a unitary manner has no role in
Medical Practice. “Connect the Dots!”
PIVOTAL PATHOGENESIS TO CONSIDER IN
A THERAPEUTIC APPROACH TO OBESITY

• Metabolic Syndrome X
• Inflammation
• Oxidative Stress
• Toxic Lipogenesis
• Energy regulation
• Thermogenesis
REDEFINING SYNDROME X
• Classic Definition: Obesity,
Hypercholesterolemia, High
Blood Pressure, Linked by
Insulin Resistance.
• Syndrome X, Y and Z….., an
expanded definition
incorporating a novel unifying
concept of common diseases
 THE PUBLIC HEALTH RISK
• Syndrome X increases risk for :
Type II Diabetes Mellitus
Cardiovascular Disease
Cardiovascular Deaths
Deaths from ALL CAUSES
Am.J.Epidemiol, 148, 958, 1998.
 INTEGRATIVE MEDICINE FOR
SYNDROME X

“While proper management of the

individual abnormalities of this
syndrome can reduce morbidity and
mortality, it seems unlikely that
management of the individual
abnormalities of this syndrome
provides better outcomes than a
more integrated strategy”
CDC, Atlanta, Ga., JAMA 2002
SYNDROME X NUTRITIONAL FACTORS
• OBESITY: Thermogenic agents (Advantra Z,
Fucoxanthin), Hoodia, fiber, green tea and green coffee
bean extract, starch blocker, chromium, fat blockers
• HYPERTENSION: fiber, botanicals unpredictable
• OXIDATIVE STRESS: alpha lipoic acid, AGES, redox
balanced, hydrophilic and lipophilic
• HOMOCYSTEINE: B6, B12, folate, TMG
• INSULIN RESISTANCE: fish oil (EPA), alpha lipoic acid,
vitamin and mineral support, other agents
• BLOOD LIPID: soy, fish oil, guggul, garlic etc.
• INFLAMMATION: EPA, curcumin, Vit C etc.
 OBESITIS
• Epidemiological links between obesity
and inflammation have been proposed for
>40y, obesity is an inflammatory status
• Glucose and fat intake induce
inflammation by oxidative stress or the
activation of transcription factors.
• Reductions in macronutrient intake in
obese subjects reduces oxidative stress
and the production of inflammatory
mediators (1000kcal/day, 4 weeks or 48
hr fast).
• Managing weight control without
managing inflammation may be nihilistic
 OBESITIS
• 30% of the total amount of cytokine IL-6 is
derived from adipose tissue.
• Decrease in CRP and IL-18 are noted
with weight loss (reduction in
inflammatory biomarkers with weight loss
• EPA valuable in correct dosage with
compliance (delivery with enteric coating)
• Adipocytokines [leptin, adiponectin and
visfatin], adiponectin lowers TNF-alpha
• Final common pathway oxidative stress
: Fat tissue, normal weight mouse

:Fat tissue, from fat mouse (ob/ob)

POTENTIAL MECHANISMS OF OBESITIS
OBESITIS
 INSULIN RESISTANCE
• New concepts of inflammation-induced
insulin resistance.
• Two transcription factor signaling pathways :
1. NF-kB pathway and 2. c-Jun NH2-
terminal kinase (JNK) pathway. These
pathways are linked to the pro-inflammatory
effects of obesity and related insulin
resistance.
• Pathways are activated by pro-inflammatory
stimuli e.g. cytokines (TNF-alpha).
• Potential mediators of insulin resistance
include IL-6, IL-10, TNF-alpha, CRP, IL-8
 ENERGY BALANCE AND METABOLISM:
REGULATED BY ADIPOCYTES
• New discoveries of circulating factors that
signal energy reserves which also signal the
brain, adipose tissue, liver, muscle and the
immune system.
• Research surrounding the discovery of
leptin led to the identification of other
chemical signals eg. adiponectin, resistin,
retinoid binding protein 4, visfatin, visceral
adipose-tissue derived serine protease
inhibitor, plasminogen activator inhibitor 1,
adipsin, cytokines and chemokines, adipose
production of corticosteroids and other
complex chemical messengers.
LEPTIN PRODUCTION IN ADIPOCYTES
 “Toxic Lipogenesis” (Holt, 2003)
• A concept that toxins stored in fat
tissue alter energy metabolism and
favor weight gain (detoxification).
• The notion that the Pot Belly is a new,
useless and dangerous endocrine
organ that signals visceral adiposity
with its poisonous stores.
• Some organochemicals are growth
promoters and induce lipogenesis
• Detoxifying fat stores is difficult
DRUGS AND NUTRACEUTICALS
 Weight Loss Nutraceuticals or
Drugs are Adjuncts Only

• A large number of weight loss

products provide false promises
of a “quick fix”
• Evidence-based supplements with
variable evidence of safety and
effectiveness include: Advantra Z,
Authentic Hoodia Gordonii,
Specific Soluble Fibers.
 THE GLYCEMIC INDEX
• Calculations of the glycemic index of
food is probably a waste of time.

• Understanding factors that control

C
gastric emptying rate can result in
inference about the glycemic index.

• Slowing gastric emptying slows glucose

absorption – relevance in acute dosing
GLUCOSE TOLERANCE WITH
SOLUBLE FIBER

Holt S, et al
Effect of
Gel Fiber…
Lancet,
March 24th,
1979.
 Thermogenesis
• The process of generating heat in the
animal body (Citrus, Seaweed, etc)
• Classic thermogenics include amines that
increase metabolic rate, a function of
beta-3 receptor activity which also
induces lipolysis and amino acid uptake
in muscle eg ephedrine and synephrine
• These classic amines tend to have non-
specific adrenergic receptor function with
cardiovascular stimulatory effects.
• Ma Haung, Citrus peel and Advantra Z
Citrus Aurantium Extract With Standardized
p-Synephrine Content, Patented and
Researched in Weight Control as Advantra Z
 Advantra Z
• This extract of Citrus aurantium (bitter
orange peel) is thermogenic, lipolytic,
ergogenic, mood enhancing, appetite
suppressing and it promotes muscle
building (Peel off the Weight, HIOM 2009)
• A body of evidence indicates that Advantra
Z does not cause the same degree of
cardiovascular or CNS hyper stimulation
that led to the withdrawal of Ephedra
 Advantra Z
• Gougeon et al. (Obesity Research,
13, 2005, 1187) described an
increase in the thermic effect of food
(TEF) by amines isolated from Citrus
aurantium
• TEF increased by 29% in women
without effects on blood pressure or
pulse rate, but with measurable
increase in epinephrine excretion
UNREALISTIC
WEIGHT LOSS
EXPECTATOIN
 A LITANY OF NEW PERSPECTIVES:
2010
• Clarification of the epidemiology of
obesity.
• Fat cell regulation of energy balance
• Neuro-hormonal control of appetite.
• Fuel sensing by the CNS.
• Obesitis
• Insulin Resistance: Syndrome X
• Cancer propagation
• Drug and nutraceutical approaches
 CONCLUSIONS
• There is no successful, sustainable stand
alone intervention for weight control
• Failing to manage Metabolic Syndrome X
and its associated disorders (Syndrome X,
Y, Z…) in the overweight person is
tantamount to negligence.
• Sleep, oxidative stress, inflammation,
nutrition, exercise, behaviour modification
and detoxification are therapeutic targets.
• The “Multipronged Approach” to weight
control must be favored.