Obeppar-Alpha

Flow of the presentation

 Burden of Obesity-Globesity & Indian perspective
 Metabolic syndrome -Role of Obesity
 Current Treatment Stratergy-Unmet needs
 Effect of PPAR isoforms on different organs
 Effect of PPAR-α on Lipid metabolism,Obesity,Inflammation,Artherosclerosis & NAFLD
 Oleoylethanolamide (OEA) - As a PPAR-α Agonist
 MOA,Differenciation from other appetite suppressants,Effects on energy balance

 Pantethine
 Valine - BAIBA
 Clinical Evidences
 GLOBESITY - A “New World Syndrome”

 Obesity is the result of an energy imbalance caused by an increased ratio of caloric intake to energy expenditure.

 A metabolic disorder that is primarily induced and sustained by an overconsumption or underutilization of caloric substrate.

 This has been attributed to a trend towards more westernised dietary and life style patterns especially increased dietary food
intake and decrease in physical activity.

Pharmacological Research 60 (2009) 151–159

 Energy Homeostasis

 Energy homeostasis is maintained by a balance between caloric intake and energy expenditure.

 The disruption of energy balance due to excessive energy intake is apt to cause a number of metabolic disorders such as
dyslipidemia, obesity, type 2 diabetes, atherosclerosis, and hypertension.

Pharmacological Research 60 (2009) 151–159

 Prevalence-Growing by leaps and bounds

 Worldwide obesity has nearly tripled since 1975. In 2016, more than 1.9 billion adults, 18 years and older, were
overweight. Of these over 650 million were obese.

 Worldwide, at least 2.8 million people die each year as a result of being overweight or obese, and an estimated
35.8 million of global Disability-adjusted life years (DALYs) are caused by overweight or obesity.

 Obesity in India has reached epidemic proportions in the 21st century, with morbid obesity affecting 5% of the
country's population. India is following a trend of other developing countries that are steadily becoming more
obese. 
 How heavy we are - Indians

 States of India ranked in order of percentage of people who are overweight or obese, based on data from the 2007 National
Family Health Survey.
States Males (%) Males rank Females (%) Females rank
Punjab 30.3 1 37.5 1
Kerala 24.3 2 34 2
Goa 20.8 3 27 3
Tamil Nadu 19.8 4 24.4 4
Andhra Pradesh 17.6 5 22.7 10
Sikkim 17.3 6 21 8
Mizoram 16.9 7 20.3 17
Himachal Pradesh 16 8 19.5 12
Maharashtra 15.9 9 18.1 13
Gujarat 15.4 10 17.7 7

 Although this phenomenon is a global one, India is unique in that it has to grapple with both over- and undernutrition at the
same time. Given the rapid rise in obesity in India, it is important to know the “weight of the nation.”
 Obesity: Indian Perspective

•Obesity is rising in India

•Obesity is characterized differently in Asian Indians

•Lower obesity cut-offs and new definitions are needed for Asian
Indians

The Asia Pacific Perspective: Redefining obesity and its treatment (Feb 2000) – WHO western pacific region, International association for the study of obesity (IASO) & International
Obesity task force (IOTF). Accessed on 11-12-2015 URL:http://www.wpro.who.int/nutrition/documents/docs/Redefiningobesity.pdf
 Obesity: Indian Perspective

 The metabolic complications develop at lower value of BMI and waist circumference.

 Asian Indians have unique body composition that may underlie their tendency to develop insulin resistance, metabolic
syndrome and T2DM.

 Interventions should be as early as possible.

 Obesity Guidelines in India
 The new guidelines state that:

• BMI of 23 kg/m2 will now be considered overweight (compared to the earlier level of 25)

• BMI of 25 will be considered clinically obese (compared to the earlier level of 30)

• The waist circumference considered as unhealthy for Indian men is now 90cm or 35.4” (it is 102cm/40.1” globally)
and 80cm or 31.5” for Indian women (as opposed to 88cm/34.6”).*
$
New guidelines – released jointly by the health ministry, the Diabetes Foundation of India, the All-India Institute of Medical
Science (AIIMS), Indian Council of Medical Research, the National Institute of Nutrition and 20 other health organisations

* Individual countries are all free to interpret waist recommendations differently. Diabetes UK, for example, has suggested levels of
94cm/37” for men of white or black ethnic background and 90cm/35” for Asian men, and for women of all ethnicities of 80cm/31.5”.
The Obesity Epidemic: Prevention and Treatment of the Metabolic Syndrome,Medscape
Features of the Metabolic Syndrome

Interleukin-6
Low-grade
inflammation Obesity

(
( Cardiovascular
Type 2 diabetes
disease

Dyslipidemia Hypertension

Genetics +
lifestyle

Lemieux I and Després JP. In: PG Kopelman (ed.), Management of Obesity and Related Disorders, Martin Dunitz, 45-63, 2001
Current Treatment Stratergy
Health benefits of weight loss

Decreased risk for cardiovascular disease

Decrease glucose and maintain insulin levels

Decreased blood pressure

Decreased LDL and triglycerides

Increased HDL
 Lifestyle Factors

 In the management of obesity, lifestyle and behavioral modifications, including appropriate diet and exercise,
should always be advocated.

 The effects of lifestyle modifications on body weight are so important that, without changes in these, drug therapy
alone is bound to fail.

 Although diet and exercise habits are mainly determined by individuals, social environment also plays a crucial
role in lifestyle modifications.However, lifestyle modification alone has limited long-term efficacy.

 Most patients experience rebounds in body weight after achieving an initial success
 Potential Strategies for Anti-Obesity Drug Action
 Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment
food intake

 Blocking nutrient absorption (especially fat or carbohydrates) in the intestine.

 Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat (UCP 2) or increase energy
expenditure through the enhancement of physical activity.

 Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or
energy expenditure.

 Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented
regarding fat stores.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | NOVEMBER 2006 |

 MOA of Anti-Obesity Drugs
Mechanism of Action of Anti-
obesity Drugs

Appetite Suppression Inhibition of fat

Other Mechanisms
Absorption Increased energy
Sympathomimetic action
e.g.Phenteramine, Diethyl propion
consumption &
Fat absorption Lipase Thermogenesis
e.g Ephedrine, caffeine AntiConvulsant
Selective serotonin re-uptake inhibitors Inhibition
e.g Topiramate
e.g Fluoxetin e.g Orlistat, Cetilstat

Combined nor Epinephrine & serotonin re-

uptake inhibitors
e.g Sibutramine

Canabinoid type 1 Receptor Inhibition

e.g Rimonabant

Selective 5 HT2C Receptor Antagonist

e.g Lorcaserine

Norepinephrine,Dopamine & serotonin Re-

uptake inhibitor Li and Cheung, 2009; Cheung, 2011,Advances in obesity treatment
e.g Tensofesine
Drug MOA Adverse effects Current status
Lorcaserin Selective 5-HT2C receptor agonist Headache, dizziness and FDA approved-June
nausea 2012
Topiramate and Topiramate blocks voltage-dependent Diarrhea, possible harm to FDA approved-July
Phentermine sodium channels, glutamate receptors fetus, increased heart rate 2012
and carbonic anhydrase, and augments
GABA activity; phentermine is
sympathomimetic

Liraglutide Glucagon-like peptide 1 receptor Nausea; GI symptoms FDA approved-July

agonist 2012

Orlistat Lipase inhibitor: decreased absorption Diarrhea, flatulence, bloating, FDA approved-
of fat abdominal pain, fatty stool 1998

Naltrexone and Bupropion increases activity of pro- Nausea, constipation, FDA approved-
Bupropion opiomelanocortin (POMC) neurons. headache, vomiting, dizziness, september 2014
Naltrexone blocks opioid receptors on insomnia, dry mouth and
the POMC neurons, preventing diarrhea
feedback inhibition and increasing
POMC activity
 Weight Loss Surgery

Option for limited number of patients with clinically severe obesity.

BMI >40 or >35 with comorbid conditions
Reserved for patients in whom medical therapy has failed
Gastric restriction or gastric bypass (Bariatric Surgery)

Integrated program must be in place before and after surgery.

Patient Selection, Benefits and Complications of
Bariatric Surgery

Obesity Diabetes Operative Risks

Co-Morbidities

Obesity Surgery

Benefits: Complications:
- Weight loss - Nutrient deficiency
- Metabolic improvements - Dumping syndrome
- Mortality benefit - Hypoglycemia

Frachetti KL, et al. Curr Opin Endocrinol Diabetes Obes. 2009;16:119-124

 Anti-Obesity Drugs-Unmet Needs

 Over the past several years, there has been a great increase in the use of antiobesity drugs, although, to date, the most
promising treatment for obesity may consist of controlled energy intake and increased physical activity.

 However, there remains an urgent need for safer and more effective alternative therapies to the long-term use of these drugs,
due to unwanted side effects.

 With antiobesity therapies, increasing the fat oxidation is thought to be a good strategy. Several human studies showed that
obese patients with impaired fat oxidation failed to lose weight. Therefore, elevated fat oxidation seems to lead to weight loss.
Inflammation and Cardiovascular Disease: Is Abdominal
Obesity the Missing Link?
CRP
TNF-a ?

?
IL-6

?  Risk of acute
coronary
Adipose Atherogenic, syndrome
tissue insulin resistant
“dysmetabolic CRP:
IL-6:
C-reactive protein
interleukin-6
milieu” TNF-: tumor necrosis factor-

Adapted from Després JP Int J Obes 2003; 27: S22-4

Reproduced with permission
 Tissue expression and ligands of PPARs Family
 The PPAR Family. Peroxisome proliferator-activated receptors (PPARs) are transcription factors, belonging to the nuclear receptor
superfamily, a group of proteins that are usually activated by their respective ligands and function within the cell nuclei for controlling
metabolism, development, and homeostasis of the organism.

 PPARs have 3 isoforms in mammals, namely, 𝛼, 𝛽/𝛿, and 𝛾. Although they share structural similarity and exhibit high homology in
amino acid sequence, the three isoforms are differentially expressed among tissues. They modulate different ligand specificity, very
distinct tissue distributions, and different biological functions.

 In general, PPAR𝛼 is abundant in the liver, brown adipose tissue, heart, and kidney; PPAR𝛾 is mainly enriched in the adipose tissue
and PPAR𝛽/𝛿 is ubiquitously expressed throughout the body. Their differential distributions as well as different affinities to ligands
attribute to their distinct roles.

 Thus, modulation of PPARs activity may be an effective therapy for several diseases associated with metabolic syndrome.

Pharmacological Research 60 (2009) 151–159

Effect of PPAR isoforms (PPAR-α, PPAR-γ, PPAR-δ) on adipose tissue,
liver, muscle, and vessel wall

Arterioscler Thromb Vasc Biol. 2006;26:28-40.

 PPAR Agonist Therapeutics
 PPAR gamma agonists - insulin sensitizers for type 2 diabetes
 Approved drugs – Pioglitazone, Rosiglitazone

PPAR alpha agonists –for dyslipidemia, increase HDL, decrease TG, effects on LDL.
Approved drugs – fibrates ( fenofibrate, clofibrate)

PPAR dual agonists (alpha/gamma) – being developed for combined treatment of type 2 diabetes
and dyslipidemia
Saroglitazar, Muraglitazar, Tesaglitazar, Aleglitazar

PPAR pan agonists (alpha/delta/gamma) – being developed for type 2 diabetes and dyslipidemia
 The role of PPAR-α in lipid metabolism (1)
 PPAR-α, the first PPAR to be identified, is implicated in the regulation of lipid metabolism and glucose
homeostasis by regulating the expression of proteins involved in the transport and β-oxidation of FFAs.

 PPAR-α is expressed predominantly in liver and, to a lesser extent, in heart, skeletal muscle, and kidney, where
it appears to play a crucial role in intracellular lipid metabolism.

 Fibrates like fenofibrate or bezafibrate are weak activators of PPAR-α and are widely used to treat
hypertriglyceridemia in patients.

 Fibrates lower circulating triglyceride levels by increasing the activity of the enzyme lipoprotein lipase (LPL),
which is the key enzyme in the hydrolysis of triglycerides.

Arterioscler Thromb Vasc Biol. 2006;26:28-40.

 The role of PPAR-α in lipid metabolism (2)
 The PPAR-α form has been shown to mediate the hypolipidemic effects on lipid and lipoprotein metabolism. (For
decreasing high circulating triglyceride (TG) levels and increasing high-density lipoprotein (HDL).

 PPAR-α activation also mediates improvement of glucose and energy homeostasis, inhibition of vascular
inflammation, and correction of age-related dysregulation.

 In vivo and in vitro studies demonstrate that PPAR-α plays a central role in lipid and lipoprotein metabolism, and
thereby decreases dyslipidemia associated with metabolic syndrome.

 Researches have also indicated that PPAR-α may have antiobesity effects and improve obesity-related disorders.
Lipid metabolism by controlling the expression of PPAR-α genes

Activation of PPAR leads to increased tissue-specific expression of key genes involved in fatty acid uptake and β- oxidation.
This includes acyl-Coenzyme A synthetase, an enzyme which plays a key role in esterification of fatty acids thereby
preventing their efflux from cells, in the liver and kidney, and carnitine palmitoyltransferase type 1 (CPT-1), a pivotal enzyme
involved in fatty acid catabolism within mitochondria in metabolically active tissue such as the heart, skeletal muscle and
brown adipose tissue, which contains a PPRE in its promoter region. The net effect of this is reduction in the availability of free
fatty acids for synthesis and secretion of very-low-density lipoproteins (VLDL).

Expert Opinion on Investigational Drugs DOI: 10.1080/13543784.2017.1312339 PPAR-α agonists are still on the rise: an update on clinical and experimental finding
J.-C. Fruchart / Atherosclerosis 205 (2009) 1–8
Mechanism - PPAR-α -Antiobesity agent

Pharmacological Research 60 (2009) 151–159

 Chronic low grade inflammation and obesity

It has been shown that expression of Tumor Necrosis

Obesity is currently viewed as a Factor-α (TNF-α) is significantly higher in obese compared
state of low grade chronic to lean subjects.
inflammation elicited by changes in
the secretion profile of adipose Subsequently, it was shown that plasma levels of pro-
tissue. inflammatory proteins are increased during obesity,
whereas levels of anti-inflammatory proteins such as
adiponectin are decreased

Obesity-induced changes in adipose tissue leading to a pro-inflammatory secretion profile can

influence the progression of insulin resistance, atherosclerosis and fatty liver disease.

The role of PPARs in inflammation and obesity Thesis Wageningen University, Wageningen, The Netherlands
 PPAR-α, inflammation and atherosclerosis

 Mechanistically, PPAR-α,activation may influence the development of atherosclerosis via indirect effects on glucose and lipid
homeostasis in adipose tissue, skeletal muscle and the liver.

 Additionally, PPAR-α may have a direct effect on inflammation and atherosclerosis, by modification of the transcription factors
nuclear factor-кB (NF-кB) and activator protein-1 (AP-1).

 Cytokines such as tumour necrosis factor-α (TNF-α), interleukins and interferon-γ, which are released from T lymphocytes
during the initiation of a chronic inflammatory response, play a critical role in cellular immunity, and contribute to the early
development of plaque.

 Therefore, repression of inflammation by decreasing cytokine release could be very important in modulating the cascade of
responses in atherosclerosis.

J.-C. Fruchart / Atherosclerosis 205 (2009) 1–8

Cytokine imbalance associated with the metabolic syndrome-NAFLD

J.-C. Fruchart / Atherosclerosis 205 (2009) 1–8

 Oleoylethanolamide (OEA)-Natural PPAR-α agonists-Novel Anti-obesity
Drug
 Oleoylethanolamide (OEA), a gut-endocrine fat-derived lipid, is an endogenous ligand of PPAR-α. Synthetic PPAR-α agonists such
as the fibrates (e.g. fenfibrate) are currently used in the clinic as lipid-lowering and anti-atherogenic drugs. However, the potencies
of these compounds at PPAR-α are 500-900 times lower than that of OEA and, consequently, they do not significantly affect food
intake.

 The fatty-acid ethanolamide, oleoylethanolamide (OEA), is a naturally occurring lipid that regulates feeding and body weight.

 OEA treatment initiates transcription of PPAR-α and other PPAR-α target genes, including fatty-acid translocase (FAT/ CD36), liver
fatty-acid binding protein (L-FABP), and uncoupling protein-2 (UCP-2). Moreover, OEA decreases neutral lipid content in
hepatocytes, as well as serum cholesterol and triglyceride levels. The results suggest that OEA regulates lipid metabolism and this
effect may contribute to its anti-obesity properties.

Fan A et al. (2014) Atheroprotective Effect of Oleoylethanolamide (OEA) Targeting Oxidized LDL. PLoS ONE 9(1): e85337.
 Scaffold for the design of novel anti-obesity drugs
 Administration of OEA as a pharmacologic drug can cause (i) stimulation of lipolysis; (ii) induction of β oxidation; and (iii) increase of
fatty acid uptake through the activation of PPAR-α signaling pathway.

 OEA regulates the expression of several PPAR-α target genes: it initiates the transcription of proteins involved in lipid metabolism and
represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation.

 UCP-2 is a mitochondrial protein that uncouples respiration from ATP synthesis in liver and muscle tissues, allowing energy to
dissipate as heat. This thermogenic effect is thought to promote weight loss and may thus contribute to the anti-obesity effects exerted
by OEA

 The pharmacological profile of OEA stimulates lipolysis by activating PPAR-α suggests that this natural lipid may provide novel anti-
obesity drugs with combined anorexiant and lipolytic properties.
 Potential Strategies for Anti-Obesity Drug Action
 Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake
(represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation.)

 Blocking nutrient absorption (especially fat or carbohydrates) in the intestine.

 Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat (UCP 2) or increase energy expenditure
through the enhancement of physical activity.

 Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy
expenditure. (stimulation of lipolysis;induction of β oxidation; and increase of fatty acid uptake through the activation of PPAR-α
signaling pathway

 Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented regarding fat
stores.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | NOVEMBER 2006 |

 OEA-induced weight stabilization along with satiety

 OEA shows all of the defining characteristics of an endogenous PPAR-α agonist.

 first, it binds with high affinity to PPAR-α; second, it mimics the actions of synthetic agonists in a PPAR-α-
dependent manner; and last, under appropriate conditions, it reaches tissue concentrations that are sufficient to
activate PPAR-α.

 The results also suggest that PPAR-α activation not only mediates OEA-induced weight stabilization, but is also
responsible for OEA-induced satiety, a behavioural role that was not previously attributed to PPAR-α.
 Decreasing Meal Frequency & Size

 OEA is a well-established anorexiant factor, a lipid-based satiety signal whose increase in the lumen of the small
intestine induces a persistent and selective inhibition of food intake without known adverse reactions.

 Anorexiant agents can curb food ingestion via distinct mode of action such as the reduction of meal size ingested.

 Basically, in nonfood deprived animals, OEA administration increases inter-meal latency (decreasing meal
frequency), whereas it decreases also meal size in food deprived animals.

The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body
Weight http://dx.doi.org/10.5772/63147
 Differenciation OEA & other appetite suppressants

 OEA reduced food intake when administered peripherally but appeared to be ineffective at doing so when
administered centrally.

 This pharmacological activity differentiates OEA from other appetite suppressants, such as amphetamine and
glucagon-like peptide-1, that may cause aversion and anxiety, and, cannabinoids such as
(arachidonoylethanolamine) AEA which reduces pain and activates the hypothalamus–pituitary–adrenal axis.

 Besides inducing satiety and playing a significant role in the regulation of energy homeostasis, OEA has been
shown to inhibit gastric emptying and intestinal motility.

Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity Vol. 7, No. 3–4 2010
 Effects of OEA on energy balance
 There is a growing body of evidence to support the idea that OEA may play a important role in the control of energy expenditure
and fat utilization, mainly through its involvement in the regulation of both lipid and glucose metabolism.

 Lipid metabolism:OEA regulates the expression of PPAR-α target genes implicated in fatty acid mobilization and oxidation, as well
as redox balance during oxidation processes in important metabolic tissues such as adipose tissue, liver, muscle and gut.

 Glucose metabolism:In addition to its lipolytic effects, OEA is also involved in glucose metabolism regulation. It has been reported
to produce the impairment of glucose tolerance, and inhibit insulin-mediated glucose uptake in adipocytes.

Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity Vol. 7, No. 3–4 2010
 OEA-GPR119 activation promotes incretin secretion and enhances
peptide YY action

 OEA may reach islets through GPR119 localized in PP-cells (pancreatic polypeptide producing cells), which
stimulate PPY secretion.

 PPY, in turn, exerts a variety of regulatory actions in the gastrointestinal tract including the inhibition of pancreatic
exocrine secretion, gallbladder contraction, and modulation of gastrointestinal motility.

 These effects together slow down the digestive process and the entry of nutrients into the circulation, preventing
the postprandial elevation of blood glucose.

Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity Vol. 7, No. 3–4 2010
Proposed mechanisms of OEA action

Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity Vol. 7, No. 3–4 2010
 Pantethine-Lipid regulator (1)

 Pantethine is a naturally occurring physiological compound synthesized in the body from pantothenic acid (vitamin B5).

 Pantethine is considered to be the most active form of vitamin B5 because it contains the sulfhydryl-group needed for biological
activity in Coenzyme A (CoA).

 It is derived from pantothenic acid by the addition of cysteamine and has well documented effects in LDL-C, HDL-C and
Triglycerides.

 Pantethine acts by accelerating the use of fat as an energy source and inhibiting cholesterol synthesis.
 Pantethine-Lipid regulator (2)

 It is the fundamental component in synthesis of Coenzyme A which is involved in many enzymatic pathways
including fatty acid oxidation, etc. hence accelerate the use of FA as energy.

Thus, Pantethine is a key factor in

 Further, it inhibits cholesterol maintaining optimal
synthesis by inhibiting blood
HMG- lipid balance.
CoA reductase enzyme – the rate limiting enzyme of
the mevalonate pathway.

 According to the trials, the daily intake of Pantethine of 900 mg /day for 12 weeks reduces 15.1% total serum
cholesterol, 20.1 % LDL-C, 32.9% serum TG and increases 8.4 % HDL-C when measured at forth month.
 Valine- β-aminoisobutyric acid (BAIBA)

 BAIBA can also be generated by catabolism of the branched-chain amino acid valine.

 It is an amino acid that is not naturally found in the genetic code of any organism — it’s formed when either
thymine or valine are broken down.

 BAIBA’s effects are based around metabolic changes in the liver and in fatty tissue:
 Changes the characteristics of energy storing white adipose tissue into energy burning brown-like adipose tissue via PPAR-α
 Increases hepatic beta oxidation  though a PPAR-α mediated mechanism.
 Valine - BAIBA-lipid metabolism
 BAIBA acts on PPAR-α to perform the roles of white adipose browning, increase of beta oxidation and decrease
in fat creation.

 PPAR-α is a major regulator of lipid metabolism in the liver, involved in the breakdown of fatty acids and
increases in energy utilisation. It performs its work through increasing fatty acid transport, binding, and activation
and through beta oxidation.
This randomized, double-blind, controlled clinical trial was carried out on 60
healthy obese people from November to May, 2016 in Tabriz, Iran. Individuals
between the ages of 18 and 59 years and with a body mass index (BMI)
between 30 and 40 kg/m2
The main finding of this study is that supplementation with
2 x 125-mg OEA capsules for 8 weeks enhanced the
expression of the PPAR-α gene, improved anthropometric
measurements (weight, BMI, waist circumference, and fat
mass) and appetite sensations (hunger, desire to eat
foods, and cravings for sweets decreased, and fullness
increased).

Considering the many beneficial effects of OEA in various

metabolic pathways, its use as a
complementary approach to weight loss could be effective
in suppressing appetite and controlling weight in obese
people
 OBEPPARALPHA
(YAGONA 285 mg Capsules)
A Patent Applied Formulation for OBESITY
 DESCRIPTION-
OBEPPARALPHA contains Yagona 285 mg Capsule, is novel approach to manage obesity. It is a patent applied blend that contains Oleoylethanolamide,
Pantethine, Valine.

 INDICATION-
OBEPPARALPHA due to its lipid modulating and anti inflammatory actions is been indicated for obesity management including weight loss and weight
maintenance.

 DOSAGE-
Recommended daily dose of OBEPPARALPHA is 1-2 capsules daily.

 COMPOSITION-
OEA : 200 mg
Pantethine:75 mg
Valine:10 mg
 Quick Revision
 Administration of OEA as a pharmacologic drug can cause (i) stimulation of lipolysis; (ii) induction of β oxidation; and (iii) increase of
fatty acid uptake through the activation of PPAR-α signaling pathway.

 OEA regulates the expression of several PPAR-α target genes: it initiates the transcription of proteins involved in lipid metabolism and
represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation.

 UCP-2 is a mitochondrial protein that uncouples respiration from ATP synthesis in liver and muscle tissues, allowing energy to
dissipate as heat. This thermogenic effect is thought to promote weight loss and may thus contribute to the anti-obesity effects exerted
by OEA

 The pharmacological profile of OEA stimulates lipolysis by activating PPAR-α suggests that this natural lipid may provide novel anti-
obesity drugs with combined anorexiant and lipolytic properties.
 Quick Revision
 Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake
(represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation.)

 Blocking nutrient absorption (especially fat or carbohydrates) in the intestine.

 Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat (UCP 2) or increase energy expenditure
through the enhancement of physical activity.

 Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy
expenditure. (stimulation of lipolysis;induction of β oxidation; and increase of fatty acid uptake through the activation of PPAR-α
signaling pathway

 Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented regarding fat
stores.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | NOVEMBER 2006 |

 Quick Revision
 OEA reduced food intake when administered peripherally but appeared to be ineffective when administered centrally. This
pharmacological activity differentiates OEA from other appetite suppressants which may cause aversion and anxiet and activates
the hypothalamus–pituitary–adrenal axis.

 OEA binds with high affinity to PPAR-α (500-900 times higher than fibrates); second, it mimics the actions of synthetic agonists in
a PPAR-α-dependent manner; and last, under appropriate conditions, it reaches tissue concentrations that are sufficient to
activate PPAR-α.

 OEA with Pantethine & Valine have a synergistic effects on Obesity,Lipid metabolism, Fatty liver disease with inflammation &
Diabetes