Neurobiology as the etiopathogenesis of obesity

Abstract

The neuroregulation of eating behavior is a complex process encompassing homeostatic, hedonic, and executive functions. The homeostatic system balances energy through the gut-brain axis, signaled by incretins and hormones such as ghrelin (hunger) and leptin (satiety). Hedonic control is based on the reward, desire, and pleasure generated by food intake, involving dopaminergic circuits. The executive function of the prefrontal cortex constitutes the final arbiter of decisions related to food.

Appetite is based on three pillars: searching, consuming, and completing the meal. The search for food is driven by hypothalamic neurons in response to an energy deficit. Food intake is regulated by GABA neurons, and the pleasurable reinforcement of food completes the cycle with satiety, triggered by post-ingestion signals such as gastric distension and intestinal peptides like glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), and cholecystokinin (CCK), among others, which aim to stop further food intake. Taste acts as a guardian, detecting nutrients or toxins and influencing satiety according to flavor intensity. Modern ultra-processed foods increase the rate of food intake, exceeding the response capacity of the satiety system. Obesity, defined as a neurobiological disease, involves a "vulnerable brain" coexisting with an obesogenic environment that alters reward circuits and generates resistance to key hormones like leptin, in addition to neuroinflammation that disrupts neuroregulation.

There are critical developmental windows for programming these circuits, beginning in the embryonic stage and with maternal nutrition. During childhood, early sensory experiences shape lifelong food preferences related to obesity and diabetes in adulthood.

Obesity treatment focuses on complications and dysfunctional body fat mass, placing greater emphasis on body composition. Weight loss activates defensive biological responses that make it difficult to maintain a lower weight in the long term.

Integrating neuroscience with nutrition is essential for creating effective public policies and dietary guidelines. Understanding the mechanisms of food addiction and the subjective value the brain assigns to nutrients is key for the future. Only through a multidisciplinary approach can we address the epidemic of obesity and related chronic diseases. Science is now seeking to personalize interventions to restore the patient's metabolic homeostasis.