Role of Leptin in Obesity Management: Current and Herbal Treatment

Abstract

Obesity is an excessive accumulation of fat in the body associated with numerous complications such as development of hypertension, type 2 diabetes (T2DM), dyslipidemia, sleep apnea, and respiratory disorders; and ultimately life-threatening cardiovascular disease (CVD), stroke, certain types of cancer and osteoarthritis. In 2016, more than 1.9 billion adults aged 18 years and older were overweight. Of these, over 650 million adults were obese, that is over 39% of men and 40% of women were overweight. Rapid rise in obesity cases in both developed and developing countries and people suffering from it needs rapid and complete cure form it without any side effects. Herbal medicine has been used for the treatment of disease for more than 2000 years, and it has proven efficacy. Many studies have confirmed that herbal medicines are effective in the treatment of obesity. Various plants from different families and several phytochemical constituents are responsible for the anti-obesity activity such as fenugreek cinnamon, cardamom, ginger, etc. Present work mainly cover herbal species having leptin-stimulating potential for weight management, importance of leptin, its mechanism of action, current and herbal treatment for effective weight management.

1. Introduction

In 2016, more than 1.9 billion adults aged 18 years and older were overweight. Of these over 650 million adults were obese i.e. 39% of adults and over (39% of men and 40% of women) were overweight. Overall, about 13% of the world’s adult population (11% of men and 15% of women) were obese in 2016. Obesity is quantities in terms of Body Mass Index (BMI), which is defined as the ratio of the weight and the square of height and is a measure of body adiposity [1]. The incidence and prevalence of obesity, are rising both in developed and developing countries. Although globalization has resulted in substantial improvements in quality of life and food security, as well as reductions in poverty, unintended consequences of globalization are also driving the obesity epidemic. Among the multiple factors contributing to its etiology, the sedentary life styles, white collar jobs, lack of exercise, psychological factors, excess consumption of junk food and the consumption of energy rich diets are the major ones. Obesity is excessive accumulation of fat in the body associated with numerous complications such as development of hypertension, type 2 diabetes (T2DM), dyslipidemia, sleep apnea, and respiratory disorders; and ultimately life-threatening cardiovascular disease (CVD), stroke, certain types of cancer and osteoarthritis. Currently there is rapid rise in obesity and related severe diseases mainly due to drastic changes in lifestyle, living standard and modern diet. However rapid urbanization, economic revolution and free trade liberty are main reasons behind this. Nowadays in low and middle income nations there is drastic change in nutritional values mainly due to getting proteins and fats obtained from animals, added sugars and refined grains. Due to obscure etiology, the pharmacological treatment of obesity has been a particularly challenging task. Reducing body weight by lifestyle alteration is advisable, but sometimes drug intervention is necessary. Combating obesity is going to requires coordinated efforts from the international community, governments, industry, health-care systems, schools, urban planners, agriculture and service sectors, the media, communities and individuals. Further, the cause of concern is the non-availability of drugs for its treatment and the short-term efficacy and limiting side effects of the available drugs. Drugs used for obesity management are mainly classified in to metabolic promoters, digestion and absorption blockers, central appetite suppressants and obesity gene product inhibitors. However drugs used for obesity management specifically affects monoamine neurotransmitters leads to habit forming, dependence or abuse [2]. Anti-obesity drugs have been studied profoundly for decades. The need for adjunctive therapies for weight loss has accelerated the progress in the pharmaceutical industry worldwide. Weight loss drugs may appear to be a solution to obesity. However, possible side effects or adverse drug reactions are always a big public health concern and also a major barrier to the development of new drug products. Obesity, which is broadly refers to excess body fat, and ranked as the fifth foremost reason for death globally. Overweight and obesity are major lifestyle illness that leads to wide variety of chronic diseases, which may include cancers, metabolic syndrome, diabetes, cardiovascular diseases, osteoarthritis, gout, breathing problems etc. The World Health Organization predicted about 30% of death occurring in whole world will be initiated with lifestyle disease in 2030 and can be stopped by appropriate identification and conveying associated risk factors. It is therefore essential to detect and diagnose obesity as early as possible [3]. Worldwide more than 1.9 billon adults are overweight and 650 million are obese. Approximately 2.8 million deaths are reported as a result of being overweight and obesity. This is major health related problem in both developed and developing countries. In India more than 135 million individuals were affected by obesity. The study of total body fat accurately requires sophisticated technology. The World Health Organization (WHO) have acquire body mass index, which is calculated by dividing the body weight in kilograms (kg) by the square of the height in meters (m), as a surrogate measure of total body fat (Table 1). With this index, obesity is defined when the value is equal to or more than 30 Kg/m² [4]. Formula: BMI = Weight/Height².

Weight status	Body mass index in kg/m^2
Under-weight	<18.5
Normal range	18.5–24.9
Over-weight	25.0–29.9
Obese	≥ 30
Obese class-I	30.0–34.9
Obese class-II	35.0–39.9
Obese class-III	≥40

Table 1.

Classification of weight based on body mass index.

2. Leptin

The discovery of leptin 15 years ago generated great excitement that the treatment for obesity had been found, and thus, this prototypical adipocyte-secreted protein/cytokine was named leptin after the Greek word “leptos” for thin. Leptin is a group of 167 amino acids in human leptin gene mainly made up of adipose tissue and enterocytes which mainly regulate energy balance by inhibiting hunger. It is released by white adipose tissue and leptin level is key indicator of body fat. As like other hormones leptin is secreted at regular temporal pattern i.e. highest secretion in early morning and evening. Leptin mainly is an indicator of how much energy stored in fats and caloric intake [5].

2.1 Types of leptin receptors

1. There are mainly three types of leptin receptor i.e. the OBRa, OBRb, and OBRb with formulation (OBRb-fa), by measurement of the levels of tyrosine phosphorylation of STAT3 (signal transducers and activators of transcription 3) and MAPK (mitogen-activated protein kinase).

2. This receptors are induced by leptin stimulation of CHO cells stably expressing the OBR (CHO-OBRb, CHO-OBRa, or CHO-OBRb-facells).

3. As the result of leptin stimulation, enhanced levels of tyrosine phosphorylation of STAT3 [6].

2.2 Mechanism of action of leptin

Leptin (Greek word leptos– thin) also known as “Ob gene” that is located on chromosome number 7. Main role of leptin is to achieve an energy balance in the body. Leptin binds to receptors in brain and performs several actions that may prove that leptin is important in treating obesity.

It works through two distinct types of neurons in arcuate nucleus of hypothalamus.

1. POMC/CART (Pro-opiomelanocortin/cocaine and amphetamine regulated transcripts) neurons

2. NPY/AgRP (Neuropeptide Y/Agouti—related peptide) neurons

Leptin stimulates POMC/CART neurons to produce anorexigenic neuropeptide: melanocytes stimulating hormone that results in

1. Endocrine changes

2. Increase sympathetic nerve activity

   This stimulates energy expenditure.

   Leptin inhibits NPY/AgRP neurons that produce feeding—inducing (orexigenic) neuropeptide: NPY that results in inhibition of food intake.

The binding of leptin to its receptor initiates numerous signal transduction pathways and as result, regulates a range of cellular function in body (Figure 1). leptin receptor as a member of type 1 cytokine receptor family, signals via Janus kinase family of tyrosine kinase. Leptin induced dimerization alters the intracellular domain confirmation to increase its affinity for cystolic JAK. After this JAK activate and phosphorylate tyrosine residue, then it bind another free moving protein STAT. This also phosphorylate by JAK. Pairs of phosphorylated STAT dimerize and translocate to the nucleus to regulate gene transcription resulting in a biological response of leptin [7, 8].

Figure 1.

Mechanism of action of leptin.

3. Pathophysiology

Three parts.

1. Peripheral afferent system (PAS)

2. Control processing.

3. Peripheral efferent system (PES)

Through PAS

3.1 Peripheral appetite suppressing signal

1. It act through secrete leptin and adiponectin.

   In obese person the level of adiponectin is low and it involve in thermogenesis.

2. GUT hormone secretes insulin, amylin and glucagon like peptide.

3.2 Peripheral appetite stimulating signal

A. It acts through Gut hormone secrete ghrelin, obestatin. Anorexigenic via ObRb receptor expressed in brain and peripheral tissue which is binding in the hypothalamus, leptin activates a complex neural circuit comprising of anorexigenic (that is appetite suppressing) and orexigenic (that is appetite stimulating) neuropeptide to control food intake. Loss of melanocortin 4 receptor (MC4R) function, a key MCR expressed in the hypothalamus, is the most common genetic cause of obesity in humans [9].

3.3 Through PES

Though PES the regulation is controlled by negative feedback mechanism. Though food intake and energy expenditure. Change in appetite or drastic reduction in hunger mainly due to not only activation neuron via binding to the melanocortin receptor (MCR) by leptin which acts on proopiomelanocortin (POMC) leads to release of melanocyte stimulating hormone (α-MSH) in to synapse but also inhibition of neuropeptide-Y (NPY)/agouti related peptides (AgRP) synthesis in neurons which negatively affects agonistic potential of AgRP on MCR resulting in to suppression of appetite (Figure 2) [10].

Figure 2.

Regulation of appetite by leptin acting on the nucleus arcuatus of the hypothalamus. Proopiomelanocortin (POMC), neuropeptide Y (NPY), Agouti-related protein (AgRP), melanocortin receptor (MCR), gamma amino butyric acid (GABA).

4. Current treatment for obesity management and its effects

Anti-obesity drugs have been studied profoundly for decades [11, 12, 13]. The need for adjunctive therapies for weight loss has accelerated the progress in the pharmaceutical industry worldwide. Weight loss drugs may appear to be a solution to obesity. However, possible side effects or adverse drug reactions are always a big public health concern and also a major barrier to the development of new drug products. Some of the antiobesity drugs commercially available are orlistat, lorcaserin, sibutramine, rimonabant, metformin, exenatide, pramlintide etc. These drugs have a wide variety of severe side-effects including development of cardiovascular problems, restlessness, insomnia, faulty bowel movements, pain in stomach, psychiatric problems etc. Ideally anti-obesity agent would be such as to produce weight loss which can be retained, but with minimal side effects. Medication for short term weight management or selected medications used off label to promote weight loss mentioned in (Table 2) and Medication for long term weight management are listed in (Table 3).

Drugs	Mechanism	Effect on weight	Adverse effect	Status
Phentermine	Sympathomimetic amine (appetite suppressant)	3.6 kg placebo subtracted weight loss in studies ranging from 2 to 24 weeks	Insomnia, tremor, increase BP and pulse rate, headache, palpitation, constipation.	Diffusion controlled release preparation is available
Diethylpropion	Sympathomimetic amine (appetite suppressant)	3.0 kg placebo subtracted weight loss at 6–52 weeks	Insomnia, tremor, increase BP and pulse rate, headache, palpitation, constipation.	Currently approved drug for short term
Zonisamide	Anti-convulsant drug	5.0% placebo subtracted weight loss at 12 weeks	Increase nervousness, sweating, tremors, gastrointestinal adverse effects, hypersomnia, fatigue and insomnia	Used off—label
Topiramate	Anti- convulsant drug	6.5% placebo subtracted weight loss at 24 weeks	Paresthesia, dizziness, altered taste, fatigue, memory impairment, somnolence, anorexia and abdominal pain	Used off—label

Table 2.

Medication for short term weight management or selected medications used off label to promote weight loss.

Drugs	mechanism	Effect on weight	Adverse effects	status
Orlistat	Pancreatic lipase inhibitor	2.9 kg placebo subtracted weight loss at 1 year	Abdominal pain, bloating, flatulence, oily stools, diarrhea, decrease absorption of fat soluble vitamins	Approved drug for long term weight management
Liraglutide	GLP-1 analogues	7.2 kg Placebo: 2.8 kg	Nausea, and thyroid C-cell focal hyperplasia and medullary thyroid tumor	Approved for treatment of obesity
Tesofensine	Anti-convulsant agent	11.2 kg Placebo: 2 kg	Nausea, dry mouth, headache, insomnia, diarrhea and constipation	Phase 3
Cetilistat	Anti-convulsant agent	4.3 kg Placebo: 2.8 kg	Abdominal pain, fecal urgency and diarrhea	Phase 3
Phentermine-topiramate	Unknown	Verage placebo-subtracted weight loss 8.6%	Combination sympathomimetic and carbonic anhydrase inhibitor / Decreases appetite and binge eating behaviors	Approved in 2012
Bupropion/Naltrexone	Naltrexone is opiate antagonists, and bupropion is an antidepressant	7.2–10.1% (24 weeks)	Nausea, dizziness, insomnia, dry mouth, bowel changes	Approved in 2014
Gelesis100	Superabsorbent hydrogel particles of a cellulose-citric acid matrix / Increases fullness.	6.4% in 6 months	No significant Risk designation	Approved in 2019
Setmelanotide (Imcivree)	Melanocortin 4 receptor agonist	weight loss 12.5–25.6%	Melanocortin-4-receptor agonist / Decreases appetite	Approved in 2020
Semaglutide (Wegovy)	Glucagon Like Peptide-1 receptor agonist	weight loss 8%	Nausea, diarrhea, vomiting, Constipation, abdominal (stomach) pain, headache, fatigue.	Approved in 2021

Table 3.

Drugs/medical devices long term weight management [12, 13, 14].

5. Herbal treatment

Herbal medicine has been used for treatment of disease for more than 2000 years, and it has proven efficacy [4, 5, 15, 16, 17]. Many studies have confirmed that herbal medicine is effective in the treatment of obesity, but the mechanisms are not clear. In present work an attempt will be done to develop herbal formulation containing different types of spices. It is a doubtless fact that various plants from different families and several phytochemical constituents are responsible for the anti-obesity activity. Current treatment of obesity includes various marketed formulations which have hazardous side effects such as high blood pressure, agitation, diarrhea, sleeplessness, liver damage, rectal bleeding, faster rate palpitations, closed-angle glaucoma, Insomnia etc. which can be overcome by using herbal formulation. Herbal medicine has been used for treatment of disease for more than 2000 years, and it has proven efficacy. Many studies have confirmed that herbal medicine is effective in the treatment of obesity. But the mechanisms are not clear. In present work an attempt will be done to develop herbal formulation containing different types of spices. It is a doubtless fact that various plants from different families and several phytochemical constituents are responsible for the anti-obesity activity⁴ Natural herbs gives not only anti-obesity effect but also other health benefits, such as anti-diabetic and anti-hyperlipidemic activities. It is anticipated that the availability of many natural sources will provide a beneficial basis for developing novel anti-obesity products. Nature is loaded with dozens of herbs and spices—from the very common black pepper to the exotic turmeric. Along with amazing health benefits they have to offer, herbs and spices also add flavor and aroma to our food and dishes.

Research has also shown that herbs and spices have the potential to boost metabolism, promote satiety (read: contentment), aid weight management and improve the overall quality of diet. Very few researchers focus on exact molecular level mechanism responsible for anti- obesity activity. Therefore, the growing threat of obesity to global health is encouraging scientists and researchers to put more effort into finding an efficient mechanism of action at molecular level. It is anticipated that there is abundant room for further contributions by researchers to establish the molecular mechanism of new natural anti-obesity agents. Urgency of a novel, nontoxic means needs to be developed to control obesity. Various plant products have been found to be effective in controlling obesity. A good portion of fruits, vegetables, spices and herbs need to be included in the regular diet. Plant derived molecules or phytochemicals are blessed with strong anti-obesogenic, anti-carcinogenic and anti-inflammatory properties. Thus they may serve as a nontoxic and cost-effective method to tackle obesity. These molecules target various pathways that are intricately linked to the process of adipogenesis. This review aims to elucidate the beneficial role of dietary food nutrients in control of obesogenicity. Following are the herbs which stimulate leptin in obesity management.

5.1 Cinnamon

Cinnamomum-verum (cinnamaldehyde)

Cinnamon is most widely used and popular weight loss herbs due to its sugar stabilizing potential which rapidly increase rate of metabolism of fats and rapidly reduces hunger pangs which has excellent for obesity management.

5.2 Ginger

Zingiber officinale (6-gingerol)

Ginger acts as a potential body cleanser which remove the food logged in the digestive system and avoid fat storage resulting in to weight loss and obesity management.

5.3 Cardamom

Elettaria cardamomum (I,8-cineole)

Cardamom boosts metabolism and helps the body burn fat more effectively and Managing conditions like indigestion, constipation, and water retention, elaichi makes for an important weight loss. Cardamom improves rate of metabolism which results in to increasing potential of our body to burn fat which ultimately helpful for weight management.

5.4 Turmeric

Curcuma longa (Curcumin)

Curcumin is safest yellow orange colored material obtained from turmeric having potential role in increase in rate of metabolism, stimulate leptin and adiponectin. Curcumin drastically reduces rate of fat formation and accumulation which ultimately lower total body fat which avoids weight gain.

5.5 Acai berry

Euterpe oleracea containing phenolic acids such as vanillic acid has important role in obesity management. It avoids excessive storage of fat in body and also prevents obesity-induced hepatic steatosis regulating lipid metabolism by increasing cholesterol excretion which is helpful for maintaining weight in control.

5.6 Nettle leaf

Urticadioica (Acetylcholine)

It has tremendous fat burning potential which helpful in maintaining the weight also nettle leaf contains vitamins like C and A which provide nutritional powers along with bold purifying property of nettle leaf.

5.7 Guarana

Paulliniacupana (Caffein)

Guarana improves rate of metabolism which directly results in to obesity control also it suppress genes that aid fat cell production and promote genes that slow it down. Caffein mainly acts on central nervous system prevent overeating due to tension and emotions.

5.8 Cayenne pepper

Capsicum annuum (Capsaicin)

This spice includes a compound called as capsaicin which helps to burn fat and suppresses your hunger cravings. According to a research done by Prudue University—cayenne is effective in weight loss, because it increases body’s metabolism activity which causes the body to burn more calories.

5.9 Cumin

Cuminum cyminum (Cumin aldehyde, phellandrene)

Cumin play a vital role in fat burning as it rapidly increases rate of burning calories by increasing rate of metabolism and prominent improvement in rate and extent of digestion. It has also play vital role in boosting immune system.

5.10 Ginseng

Panax ginseng (Ginseng saponin)

Ginseng mainly acts on leptin, insulin and adiponectin which mainly enhance rate metabolism of fats and cholesterol. Ginseng not only play important role in obesity management by acting on angiogenesis but also enhance energy level speed up rate and extent of metabolism.

5.11 Black pepper

Piper nigrum (Piperine)

Piperine is the main bioactive compound that mainly responsible for obesity management. Piperine significantly increases rate of metabolism and burn fat at faster rate mainly due to it improves mRNA expression associated with adipose tissue which is associated with lipogenesis resulting in to improvement in lipid metabolism related to genes specifically in visceral fat.

5.12 Dandelions

Taraxacum (chicoric acid, chlorogenic acid)

Dandelions primarily reduces total cholesterol level and level of fat in liver which is significant in treating obesity related disorders. It also improve rate of digestion and extent of metabolic activities.

5.13 Flax seeds

Linum usitatissimum (Omega 3 fatty acid)

Flaxseeds acts as a bulking agent and gives you a feeling of fullness. Thus, they prevent you from overeating and help you to lose weight.

5.14 Guar gum

Cyamopsis tetragonoloba (Sugars of galactose and maltose)

Guar gum helps in managing diabetes and aids weight loss. It helps to improve the digestion process and gives you a feeling of fullness.

5.15 Garcinia

Garcinia gummi-gutta (Ethyl acetate & hexane moiety)

This fruit promotes appetite suppression and prevents production and deposition of fat. Choose whole food rather than other variants.

5.16 Mustard

Brassica nigra (carotenoids (zeaxanthin, lutein, β-carotene))

Mustard is a very good weight loss herb, as it helps to fasten body’s metabolic activity.

5.17 Cocos nucifera (caprylic acid)

Coconut oil helps to increase your metabolic speed, which further aids in releasing energy and promoting weight loss.

5.18 Fennel seeds

Foeniculum vulgare (anethole.)

These tiny seeds aid in digestion and help to regulate your hunger. Besides, it also helps in cleansing your liver.

5.19 Psyllium

Plantago ovate (hemicellulose, arabinoxylans)

This is a very safe weight loss agent. These seeds make you feel fuller for a longer time and slow down the absorption of simple carbs.

5.20 Hibiscus

Hibiscus rosa-sinensis (anthraquinones)

Hibiscus is loaded with various obesity fighting agents like chromium, ascorbic acid and hydroxycitric acid (HCA).

6. Conclusion

Nowadays there is drastic rise in Incidences and prevalence of obesity in both developed and developing countries and people suffering from it need rapid and complete cure form it without any side effects. Herbal treatment stimulating leptin acts as competent alternative to current treatment without any side effects using resources form natural origin.

Acknowledgments

The authors are thankful to Department of Pharmaceutics Gajanan Maharaj College of Pharmacy Mahagaon, and Trustees of Sant Gajanan Maharaj College of Pharmacy Mahagaon for providing required guidance and support.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

Special thanks to Shvtej S. Galatage for continuous support throughout the work.

Abbreviations

AgRP	agouti-related protein
BMI	body Mass Index
CART	cocaine and amphetamine regulated transcripts neurons
T2DM	type 2 diabetes mellitus
CVD	cardiovascular disease
GABA	gamma aminobutyric acid
MAPK	mitogen-activated protein kinase
MCR	melanocortin receptor
NPY	Neuropeptide Y Agouti-related
OBRa, OBRb, OBRbfa	Obesity Receptor a, b and fa respectively
PAS	Peripheral Afferent Nervous System
PES	Peripheral Efferent Nervous System
POMC	Proopiomelanocortin
WHO	World Health Organization
STAT3	signal transducers and activators of transcription 3