Insights from experts on the neurobiological processes involved in appetite regulation

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In a recent report of a meeting published in The American Journal of Clinical Nutrition, researchers summarized the main findings related to the neurobiological regulation of appetite presented at the 23rd Harvard Nutrition Obesity Symposium in June 2022.

Study: The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets: a Report from the 23rd Annual Harvard Nutrition Obesity Symposium. Image Credit: Ann Haritonenko/Shutterstock.com
Study: The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets: a Report from the 23rd Annual Harvard Nutrition Obesity Symposium. Image Credit: Ann Haritonenko/Shutterstock.com

Background

Obesity prevalence is rising at an alarming rate among adults as well as children globally, increasing the health burden of obesity-associated chronic medical conditions such as diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.

Existing pharmacological, behavioral, lifestyle, and surgical interventions for managing obesity are limited by their availability, tolerability, costs, and contraindications. An improved understanding of the neurobiological regulation of appetite and calorie intake can aid in developing more effective obesity interventions.

About the review

In the present report, researchers elucidated hormonal, genetic, and neural pathways that contribute to appetite and body weight regulation, indicating probable molecular targets to further investigate for developing treatments to prevent and manage obesity.

Genetic and hormonal influences on body weight and appetite

Environmental and social factors that strongly affect the balance of energy consumption and utilization influence obesity and are modulated by monogenic or polygenic factors involving genes that regulate key homeostatic appetite pathways (such as the leptin, ghrelin, and melanocortin pathways). Studies have reported greater body weight and concordance of fat distribution among identical twins compared to non-identical ones.

Hormones and neural signals regulate food intake and appetite centrally by activating the brain's homeostatic (hypothalamic), cognitive, and hedonic [nucleus accumbens (NAcc)-mediated and reward-based], pathways, mediating energy homeostasis, cognitive regulation of appetite, and processing rewards, respectively. Melanocortin pathway components are critical regulators of appetite homeostasis as well as reward circuitry.

In the non-hunger state, the leptin hormone releases alpha-melanocyte-stimulating hormone (α-MSH) by binding to its receptors on the outermost layer of proopiomelanocortin (POMC) neuronal cells.

The α-MSH attaches to the melanocortin-4 receptors (MC4R) of the paraventricular nucleus (PVN) to reduce dietary consumption by triggering satiety-regulating neuronal cells of the lateral parabrachial nucleus (LPBN).

Genetic deficiencies in the MC4R genes and POMC neuronal regulatory genes may cause obesity, and semaglutide, an MC4R agonist, can effectively reduce weight. Furthermore, leptin controls dietary intake by regulating neuronal activities of the striatal reward system, involving the NAcc and caudate putamen.

On the contrary, ghrelin, an intestinal peptide secreted in the hunger state increases food intake. By attaching to the growth hormone secretagogue receptor (GHS-R) of the arcuate nucleus (ARC), ghrelin stimulates the neuropeptide Y-secreting neuronal cells and agouti-related neuropeptide (AgRP). GHS-R neuronal cells co-express with dopamine neuronal cells situated within the ventral tegmental area (VTA) to regulate hedonic hunger.

Genetic abnormalities or lesions in the PVN and altered levels of the Sim1 transcription factor may increase body weight. Sensory stimuli, such as the smell of food, rapidly suppress AgRP neuronal activity, mediated by inhibitory signals from the dorsomedial hypothalamic nucleus (DMH), which are activated by lateral hypothalamic (LH) glutamatergic neurons.

Involvement of the brain's reward circuitry, hypothalamus, and gut-brain axis in obesity

Obese individuals had higher activations of brain areas that regulate reward and motivational processes, such as the striatum, prefrontal complex, and amygdala, in response to food signals than lean individuals. The cerebellum, in particular, is a crucial driver of reward-related hyperphagic behavior. Consuming junk foods increases excitatory transmission within the striatum of obese-prone rats, increasing the calcium-permeable-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (CP-AMPAR) activity.

Individuals following low-carbohydrate diets have lower blood flow to the NAcc and thus a lower hedonic drive for food consumption, whereas high-carbohydrate diets increase the flow of blood to the NAcc. Compulsive eating, an uncontrollable desire to eat, is caused by overeating palatable food, leading to inappropriate neuronal reactions in brain reward systems and lowering dopamine levels. High-fat diets enhance cytokine release, resulting in hypothalamic microglial inflammation and weight gain. Adiposity alterations before obesity onset may also be predicted by hypothalamic gliosis.

GLP-1 agonists of the intestinal glucagon-like peptide-1 (GLP-1), such as semaglutide relax the gastric fundus, delay gastric emptying, and thereby reduce food intake. GLP-1 also has systemic effects through local neural circuits mediated by gut enteric neurons like intestinofugal neurons (IFN) and gastric nitric oxide (Nos1) neurons. Nos1 neuronal activation causes gastroparesis and suppresses appetite.

Short-chain fatty acids (SCFAs) from microbial metabolites can reduce stress reactivity caused by chronic psychosocial stress and regulate metabolism and appetite by directly influencing satiety pathways and nutrient sensing. In mice, the microbiota-gut-brain axis is also involved in regulating brain reward function and influencing interpersonal, sexual, eating, and substance abuse behaviors.

The microbiota isolated from HFD-fed mice caused profound alterations in exploratory and cognitive behavior. A Bifidobacterium strain has been found to produce metabolites that control ghrelin signaling, increase glucose tolerance, and lower cortisol levels. By restricting food consumption and promoting caloric malabsorption, bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), lowers ghrelin levels and energy intake.

Exogenous oxytocin causes weight reduction by decreasing dietary intake, increasing energy use, and promoting lipolysis. Transcranial stimulation is a treatment technique that can change behavior and help regulate dietary intake, and interventions that target the dorsolateral prefrontal cortex (DLPFC) may also reduce body weight.

Based on the report findings, several genetic, hormonal, behavioral, dietary, and neural factors contribute to obesity, which may be targeted to develop interventions for managing obesity and preventing its associated cardiometabolic consequences.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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