Obesity on a Molecular Level: A Review of Pathogenesis and Treatment Approaches

2.1.1. Leptin receptor mutation

The hormone leptin, known casually as the satiety hormone, is an adipocyte-specific hormone. Linked to the obese (Ob) gene, leptin governs the mass of adipose tissue via the hypothalamic impact on energy expenditure and satiety.^[11] It acts on the single-transmembrane-domain leptin receptor. Homozygous mutations in leptin receptor 1 or 6 encoding genes have been shown to induce early morbid obesity, hyperphagia, and diminished energy expenditure in rodents.^[12] Furthermore, these rodents also exhibited hypercortisolemia and modifications in glucose homeostasis, dyslipidemia, and hypogonadotropic hypogonadism.

While these results were shown in rodents, studies done on humans reported early-onset obesity caused by leptin deficiency driven by a leptin gene mutation. This mutation leads to the loss of both the intracellular and transmembrane domains, leaving the receptor truncated and dysfunctional. Feeding behaviour in individuals suffering from this mutation is distinguished by marked hyperphagia and ravenous, insatiable hunger.^[13]

Additionally, patients affected by this leptin receptor mutation experience no pubertal development, as well as a reported reduction in the secretion of both growth hormone and thyrotropin, which also remarkably affects metabolism. These findings show that leptin is physiologically crucial in regulating various endocrine functions in humans.^[12]

2.1.2. Ghrelin gene variations

Ghrelin, which is a hormone casually referred to as the hunger hormone, is encoded by the GHRL gene. It is secreted by the bowels and promotes the release of growth hormone, appetite, and food consumption.^[8] In a 2015 study conducted on mice, obesity induction was performed by enforcing a high-fat diet for 13 weeks. The number of preproghrelin mRNA-expressing stomach cells was reportedly 15% higher in mice fed a high-fat diet than in the chow-fed control group of mice. Furthermore, a marked increase of 30% of body fat content was reported in high-fat-diet-fed mice versus only 8% in controls.^[14]

These findings show that long-term high-fat diet consumption can lead to obesity and causes a marked increase in body fat. But what warrants more attention is how this increase in body fat manifests. Ghrelin plays a key role in this mechanism. A high-fat diet was proven to increase the number of ghrelin-expressing stomach cells, leading to increased appetite and higher food intake.

Similar to the findings observed in humans with leptin gene mutation leading to marked obesity in most individuals, ghrelin gene variations and obesity may be correlated. Arg51Gln and Leu72Met are the two polymorphisms often reported in humans. People with the Met72 allele reported earlier-onset obesity compared to patients homozygous for the wild-type Leu72 allele, which suggests that polymorphism may affect ghrelin’s activity.^[15]

2.1.3. Dopamine receptor variations

In a study done on rats, rapid weight gain and obesity were anticipated in the rats with access to a ‘cafeteria diet’ due to the marked increase in adiposity accompanied by decreased levels of striatal D2 receptors as a result of their consumption of a diet high in fat and sugar, typical of what humans with obesity would consume. Downregulation of mRNA levels for D1 and D2 receptors, as well as reduced dopamine levels in the NAc, were also observed.^[16]

D2 receptor levels in the striatum have been associated with metabolic activity in multiple cortical areas, which are critical in preserving behavioural control and managing impulsive tendencies when functioning correctly. Rats with low D2 receptors or low accumbal dopamine prefer calorically dense food, making them genetically obese.^[17] Moreover, studies performed on humans showed that individuals with the TaqIA A1 allele, which is involved with reduced expression of D2 receptors, have a higher risk of obesity. They also showed decreased striatal activation in response to palatable food, leading to a suggested decrease in impulse control.

However, it is essential to note that the opposite can also lead to obesity. A study showed that individuals with the TaqIA A2/A2 allele increased striatal responses to a palatable milkshake, which predicts susceptibility to overeating and, as a result, future obesity. All findings combined suggest that too much or too little D2 receptor-mediated dopamine signalling can increase the risk of obesity.^[18]

4.1.1. Intermittent fasting

Despite seeming as a surprisingly simple approach to such a complex problem, intermittent fasting (IF) poses a feasible way to alter gut microbiota affecting body weight. In a review by Cadena-Ullauri et al.,^[28] obesity was presented as a public health concern characterised by an imbalance between Firmicutes and Bacteroidetes. IF has been associated with multiple health benefits, namely weight loss and blood glucose regulation. Although the exact mechanism underlying its benefits is still unclear, it has been shown that it may involve gut microbiota alterations.^[29] A study by Su et al. has shown that Ramadan-associated IF diversified the gut microbiome and was associated with an increase in Clostridiales order-derived Lachnospiraceae and Ruminococcaceae.^[29] As such, IF leads to changes in the levels of microbial metabolites that act as signaling molecules contributing to a regulated circadian rhythm. This shows promise in the prevention and treatment of diseases associated with circadian rhythm dysregulation, such as metabolic syndrome and obesity.^[30] Other studies have shown that IF prompts metabolic alterations that aid in fat utilization. Notably, specific bacterial taxa exhibited complex interactions with serum metabolites involved in amino acid metabolism, focusing particularly on tryptophan derivatives and fatty acylcarnitines.^[31] Thus, IF was proposed as a promising weight-management approach that favors fat utilization. Despite having proven an association between IF and gut microbiota diversity and alterations, findings of such studies are inconsistent; the bacteria that were found to be affected by IF varied across studies, warranting further research.^[32]

4.1.2. Gene therapy

The goal of gene therapy for obesity is to increase or decrease gene product in favour of lipolysis and energy expenditure, aiming at fat reduction and weight loss. It comprises the successful delivery and expression of therapeutic genes in target cells. As discussed before, leptin is the most studied gene directly associated with obesity; it plays an important role in regulating energy intake, affecting appetite and hunger cues. It acts through binding to its receptor in the brain.^[33]

Multiple attempts have been made to make functional copies of genes to compensate for the loss of functional protein due to the previously mentioned hereditary defects in leptin receptors. Gao and Liu summarised gene therapy approaches for the prevention and treatment of obesity.^[34] For example, adenovirus-mediated leptin gene delivery effectively reversed obesity in leptin-deficient mice, although diet-induced obesity exhibited leptin resistance, which limited the treatment efficacy.^[35] Other approaches include gene transfer of BDNF, FGF21, and adiponectin, which limit weight gain and enhance glucose metabolism via improving energy expenditure and reducing inflammation. Moreover, RNA interference targeting JNK1, HIF1, and pro-inflammatory cytokines has also shown promise in alleviating obesity-related metabolic disorders. These findings provide a pre-clinical basis for treating obesity genetically.

4.1.3. Gut microbiota alteration

Novel treatment strategies for obesity based on microbiome modulation to mimic that of healthy individuals have been proposed.^[36] For instance, prebiotic fiber intake may benefit individuals with obesity and associated disorders by regulating gut microbiota. Prebiotics are generally posed as a safe and cost-effective approach to modulating the microbiota for improved host–bacterial interactions and reduced insulin resistance.^[37]

Additionally, less-studied approaches like fecal microbiota transplantation (FMT) have been proposed as promising therapeutic tools for obesity and metabolic disorders. To understand the rationale for FMT, we should first consider that obesity compromises gut microbiota diversity and increases microbial species linked with inflammation.^[38] FMT acts by directly transplanting healthy donor gut microbial strains to recipients with dysbiotic gut microbiota.^[39] Though promising theoretically, clinical studies on this approach are lacking.

4.2.1. Appetite-suppressing herbs

Garcinia cambogia and Green tea (Camellia sinensis) are two of the most extensively studied herbal appetite suppressants. Catechins, found abundantly in green tea, especially epigallocatechin gallate, have demonstrated thermogenic and fat-oxidizing effects. Combined with exercise, recent research suggests significant weight-reduction activity of certain herbs;^[41] for instance, green tea, caffeine, and yerba mate have been shown to expedite metabolic rate and augment fatty acid metabolism. Additionally, these herbs increase energy expenditure, particularly from fatty acid sources, during low and moderate-intensity exercise.

Similarly, G. cambogia extract, rich in hydroxycitric acid, is a main ingredient of various weight loss regimens.^[42] Studies have shown that G. cambogia demonstrated positive effects on weight reduction, appetite suppression, percentage of body fat, cholesterol, triglycerides, and glucose levels.^[43] However, caution should be exercised with the intake of both herbs in terms of their dosage and safety, given that the ideal dosage has not been established yet.^[43] Despite the notable popularity of these natural weight-loss supplements, their therapeutic doses and safety remain a concern.^[42]

4.3.1. Drugs that control appetite

Ghrelin administration was noted to stimulate hunger and feeding acutely, as well as chronically promote adiposity in rodents.^[44] Subsequently, the first study investigating ghrelin administration in human subjects found a strong stimulation of appetite following the administration.^[45] Therefore, ghrelin antagonism seemed like a potential target for anti-obesity therapies.

Some pharmaceutical products target ghrelin itself, whether by neutralizing it with antibodies or oligonucleotides or by affecting its synthesis in the first place by blocking O-acyltransferase.^[46] Others spare ghrelin while targeting its receptor, GHS-R1a. As a potential pharmaceutical preparation, GHS-R1a antagonists enter the central nervous system and have already shown a decrease in body weight in mice with diet-induced obesity, as well as improved glucose tolerance, following administration for 10 days.^[47] Molecules like piperidine-substituted quinazolinone derivatives were effective antagonists that lowered body weight and improved glucose tolerance.^[19]

However, not all antagonists have shown equal success; other antagonists showed little CNS penetration; CLB-678 and CCY-2308 exhibited brain concentrations of as little as 22% and 0.001% of their plasma concentrations, respectively. They still improved glucose tolerance but barely affected body weight. In fact, all tested antagonists, regardless of their apparent brain concentration, improved glucose tolerance, suggesting that the effects on glucose homeostasis may be due to the blockade of the GHS-R1a receptors in pancreatic islets.^[46] But it ultimately shows that for antagonists to be effective in lowering body weight, they have to cross the blood–brain barrier, ensuring they suppress appetite centrally.

4.3.2. Drugs that interfere with metabolism

One of the many approaches to weight loss and obesity prevention is limiting energy intake, especially by limiting fat consumption, mainly owing to its caloric density. This should be a simple solution for the obesity problem; however, restrictive diets show low compliance and only short-term results due to frequent relapses.^[48] Therefore, there have been many pharmacological interventions to prevent the absorption of certain macronutrients or generally alter their metabolism in favor of obesity prevention and treatment;^[49] like in the case of metformin, which alters glucose metabolism on a molecular level via multiple mechanisms; for instance, it activates AMP-activated protein kinase (AMPK), a cellular energy sensor that downregulates hepatic glucose output.^[50]

Orlistat (Xenical) is an example of a drug that interferes with fat absorption through the inhibition of gastric, pancreatic, and pancreatic carboxyl ester lipase, which is an enzyme that breaks down fat into absorbable parts. It performs its action mainly in the lumen of the small intestine with little to no systemic absorption. Clinical studies showed that long-term therapy with Orlistat demonstrated the highest weight loss activity compared to other agents.^[49] However, it still has some drawbacks, like inhibiting fat-soluble vitamin absorption.

4.3.3. Drugs that increase energy expenditure

Pharmacological agents that have a thermogenic effect can also be used in the treatment of obesity without dietary restriction. These agents include: ephedrine with caffeine and Beta agonists. Caffeine potentiates the adrenergic effect of ephedrine, which raises the metabolic rate, promoting weight loss. However effective these agents are, they also have many adverse effects, including cardiovascular complications.^[49]