Obesity has become a global epidemic affecting over 2 billion adults and children worldwide. The essence of obesity lies in the imbalance between energy expenditure and intake, resulting in prolonged energy surplus and storage. The implications for health are profound, encompassing conditions like type 2 diabetes, cardiovascular disease, cancer, osteoarthritis, and mental health issues, making effective treatments essential.

Current obesity treatments, aside from bariatric surgeries, are largely ineffective. However, the impracticality of widespread bariatric surgeries due to their irreversibility, potential complications, and high costs underscores the urgent need for alternative strategies.

With the obesity epidemic escalating globally, the imperative to develop effective strategies is clear. By comprehensively examining the regulatory mechanisms of energy homeostasis, this review sets the stage for potential breakthroughs in obesity treatment. As we navigate the complexities of hormones, peptides, and neurotransmitters, the hope is to uncover innovative approaches that can mitigate this pressing global health concern.

The Brain

The Brain's Command Center: The brain, especially the hypothalamus, serves as the central command center for regulating energy balance. Afferent and efferent pathways connect the hypothalamus to the brainstem and peripheral organs, allowing the brain to interpret signals related to energy status and adjust energy consumption, expenditure, and nutrient metabolism accordingly. Dysfunction in these signaling pathways is a key factor in both obesity and undernourishment.

Early research from the 1950s highlighted the significance of the brain in energy homeostasis. Lesions in specific hypothalamic nuclei led to profound changes in food intake and body weight. The brainstem, particularly the nucleus tractus solitaris and area postrema, also plays a crucial role by relaying signals from the periphery to the hypothalamus, modulating food intake based on nutritional needs. The limbic system's amygdala, an integrative center for emotions, contributes to feeding behaviors through neurotransmitters with anorexigenic and orexigenic actions.

The arcuate nucleus emerges as a pivotal player in integrating signals related to energy flux. Pro-opiomelanocortin (POMC) neurons within the arcuate nucleus express melanocortin 4 receptor (MC4R), activation of which leads to reduced food intake, thermogenesis, and weight loss. Conversely, Neuropeptide Y (NPY) and Agouti Related Peptide (AgRP) neurons in the same region promote food intake and weight gain. Disruptions in these pathways, as seen in MC4R mutations, are associated with obesity.

Other hypothalamic areas, including the paraventricular nucleus, dorsomedial nucleus, and lateral nucleus, also contribute to feeding behaviors. These regions receive and transmit signals that influence energy balance. GABA and serotonin, neurotransmitters produced in response to NPY and AgRP, play roles in regulating food intake and energy expenditure. Oxytocin, a neurotransmitter and hormone, has gained attention as an anti-obesity target, showing promise in reducing food intake and increasing energy expenditure.

While the blood-brain barrier typically protects the brain from unwanted molecules, certain hypothalamic regions, like the arcuate nucleus, have increased permeability. This allows peripheral metabolic signals to communicate with key areas of the brain involved in energy homeostasis, bypassing the traditional protective barrier.

Peripheral Signals

Leptin, a hormone primarily produced by white adipose tissue, serves as a key player in energy balance. Leptin levels correlate positively with total body fat, and its secretion is closely linked to energy status. Leptin receptors are expressed in the hypothalamus, particularly in the arcuate nucleus, where they interact with neuropeptides involved in energy homeostasis. Leptin deficiency leads to increased food intake, lower energy expenditure, and severe obesity in animal models. However, administering leptin to humans with congenital leptin deficiency has proven effective in resolving obesity. The concept of leptin resistance, prevalent in most obese individuals, poses a challenge to its therapeutic use. Research is actively exploring mechanisms of leptin resistance, offering potential avenues for combating obesity.

While insulin is well-known for its role in glucose homeostasis, it's signaling in the brain is equally crucial for energy balance. Like leptin, insulin levels are proportional to body fat, and lower insulin levels increase food intake. Insulin receptors in the blood-brain barrier provide access to the central nervous system (CNS), particularly the hypothalamus. Insulin inhibits neuropeptide Y (NPY) and stimulates pro-opiomelanocortin (POMC) neurons, contributing to its role in integrating peripheral metabolic signals. Acute infusion of insulin into the CNS reduces food intake and body weight, but chronic administration leads to insulin resistance and limited effects on obesity. Mice lacking insulin receptors in the CNS demonstrate increased food intake and diet-induced obesity, highlighting the importance of insulin in feeding behaviors.

Beyond hormonal signals, white adipose tissue provides afferent sensory input that influences sympathetic nervous system outflow. This sensory signal, received by spinal neurons projecting to the brainstem and hypothalamus, is crucial for energy homeostasis. Leptin injection into white adipose tissue enhances this sensory signaling, indicating its involvement in afferent discharge. However, the persistence of increased adipose afferent reflex in leptin resistance raises intriguing questions about the complex interplay between peripheral signals and the development of obesity.

Gut Hormones

Cholecystokinin (CCK), released in response to various nutrients, emerges as a multifunctional hormone influencing digestion and appetite. While CCK inhibits food intake and decreases meal size, animals lacking CCK exhibit normal food intake and body weight, suggesting its non-essential role in energy regulation. CCK's action on vagal neurons, integrating satiation signals with nutrient levels, highlights its complex interplay in the neural circuits governing feeding behaviors.

Ghrelin, the hunger hormone, activates NPY and AgRP neurons, stimulating appetite through the vagal afferent pathway and the nucleus tractus solitaris. The interaction between ghrelin and other hormones like leptin adds layers to its role in modulating feeding behaviors. Ghrelin's orexigenic effects, both centrally and peripherally, underscore its significance in the complex neural circuits regulating energy balance.

Peptide YY (PYY3-36), an inducer of satiety, exhibits diverse actions, including the suppression of NPY in the arcuate nucleus. Its involvement in energy expenditure and peripheral administration's impact on food intake emphasize its role in the symphony of energy homeostasis.

Glucagon-like peptide 1 (GLP-1), originating from intestinal L cells, not only enhances glucose-stimulated insulin release but also slows gastric emptying and inhibits gastric acid secretion. Acting through central and peripheral pathways, GLP-1's modulation of food intake and promotion of weight loss highlight its multifaceted contributions to energy balance.

Oxyntomodulin, derived from preproglucagon, delays gastric emptying and lowers gastric acid secretion, influencing food intake. Obestatin, originating in the gastric mucosa, inhibits food intake, prevents weight gain, and reduces gut motility. Nesfatin, found in the gut and hypothalamus, activates vagal afferent neurons, revealing its potential role in appetite regulation.

Altered Pathways in Obesity

Obesity and diabetes intertwine with disrupted pathways, including altered vagal nerve responses, inflammation, and changes in circulating signals. Leptin resistance, characterized by diminished responses in the arcuate nucleus, exacerbates obesity. High-fat diets contribute to leptin resistance, impacting the POMC neuronal population and signaling pathways. Understanding these altered responses sheds light on the intricate mechanisms underlying obesity.

The pursuit of effective obesity treatment encounters challenges in sustaining long-term weight loss through lifestyle interventions alone. While intensive lifestyle treatments yield modest success, the need for adjunctive therapies, including pharmacotherapy, becomes apparent. This section explores the evolving landscape of obesity therapeutics, emphasizing the role of pharmacological agents in achieving clinically significant weight loss and addressing associated health risks.

The initial enthusiasm for using leptin in treating obesity waned due to its rarity in congenital deficiency. However, cases of congenital leptin deficiency demonstrated remarkable outcomes, prompting exploration into agents that restore leptin sensitivity. Despite challenges in using leptin as a monotherapy, combining it with hormonal therapies like CCK, amylin, and GLP-1 has shown promise, hinting at potential future obesity treatments.

FDA-Approved Medications: Modest Success and Challenges

Currently approved medications for long-term obesity treatment exhibit limited success in research trials. Agents like lorcaserin, liraglutide, semaglutide, phentermine/topiramate, and naltrexone/bupropion offer modest weight loss, emphasizing the complexity of energy homeostasis.   

The recent surge in availability of medications approved for treatment of chronic weight management has highlighted broader issues. For instance, while the drug’s price point has put it out of reach for many, those who have started but then stopped taking the medication have experienced significant weight gain beyond their initial starting weight. More concerningly is the shortage this has caused for diabetics trying to fulfil their prescriptions of the same medication. For these people, the medication is not a choice and its availability has become a worry when the majority of the supply has been rerouted for weight loss management.

Studies exploring oxytocin as an antiobesity medication reveal its potential to activate vagal afferent neurons and suppress food intake. Additionally, receptor antagonists to melanin concentrating hormone show promise in reducing food consumption and promoting weight loss in rodent models, providing a potential avenue for future antiobesity medications.

Off-label use of medications, including bupropion, metformin, zonisamide, and pramlintide, demonstrates varying degrees of success. These medications, with mechanisms ranging from dopamine reuptake inhibition to insulin sensitization, offer additional options for obesity prevention or treatment.

Agonists of melanocortin-4 receptor (MC4R), such as setmelanotide, present a novel approach to antiobesity therapy. Clinical studies show promising outcomes, with MC4Rs playing a pivotal role in both food intake control and energy expenditure. Optimism arises from studies demonstrating increased resting energy expenditure without adverse effects on blood pressure.

Ongoing research explores centrally acting agents targeting various pathways, including NPY receptors, dopamine, serotonin, and norepinephrine. Promising drug combinations with both central and peripheral actions are under investigation, focusing on digestion interference, glucose absorption alteration, inhibition of capillary production in adipose tissue, downregulation of fat storage growth factors, AMP-activated protein kinase stimulation, beta2 adrenergic receptor stimulation, and mimetics/antagonists of gut hormones.

As the field of obesity therapeutics evolves, a multifaceted approach combining lifestyle interventions and pharmacotherapy emerges as a potential solution. However, there is currently inadequate training among healthcare providers to counsel patients on these medications, underscoring the need for comprehensive approaches. The pursuit of effective medications continues, fueled by a deeper understanding of the intricate mechanisms regulating energy homeostasis. Despite challenges, the landscape of obesity treatment is expanding, offering hope for more targeted and sustainable interventions in the future.

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