Gut peptide regulation of food intake – evidence for the modulation of hedonic feeding

Abstract

The number of people living with obesity has tripled worldwide since 1975 with serious implications for public health, as having obesity is linked to a significantly higher chance of early death from associated comorbidities (metabolic syndrome, type 2 diabetes and cardiovascular disease). As obesity is a consequence of food intake exceeding the demands of energy expenditure, efforts are made to better understand the homeostatic and hedonic mechanisms governing food intake. Gastrointestinal peptides are secreted from enteroendocrine cells in response to nutrient and energy intake, and modulate food intake either via afferent nerves, including the vagus nerve, or directly within the central nervous system, predominantly gaining access at circumventricular organs. Enteroendocrine hormones modulate homeostatic control centres at hypothalamic nuclei and the dorso-vagal complex. Additional roles of these peptides in modulating hedonic food intake and/or preference via the neural systems of reward are starting to be elucidated, with both peripheral and central peptide sources potentially contributing to central receptor activation. Pharmacological interventions and gastric bypass surgery for the treatment of type 2 diabetes and obesity elevate enteroendocrine hormone levels and also alter food preference. Hence, understanding of the hedonic mechanisms mediated by gut peptide action could advance development of potential therapeutic strategies for the treatment of obesity and its comorbidities. Key points-Enteroendocrine cells produce a range of gut peptides that have key roles in the regulation of appetite and beneficial effects on body weight. -Gut peptides are secreted as feedback to nutrient and energy intake, communicating directly or indirectly with the brain. -These peptides, some of which are also expressed in the CNS, alter food intake and reward via their widely distributed receptors. -Understanding these interactions is one of the challenges for developing effective pharmacotherapies that reduce feeding without producing negative side effects (e.g. nausea).

The Association between Peptide Hormones with Obesity and Insulin Resistance Markers in Lean and Obese Individuals in the United Arab Emirates

“…Finally, we found that fasting ghrelin was significantly lower in obese participants, and after controlling for BMI, it was negatively correlated only with WtHR [ 3 ]. Fasting ghrelin decreases with obesity and increases by diet-induced weight loss [ 19 ].…”

“…Extending from its simplistic description as an imbalance between energy intake and expenditure, obesity ensues from multifaceted interactions between genetic, environmental, psychological, lifestyle, and dietary factors, making it a complex disease to understand and address [ 2 ]. Specifically, a growing body of evidence supports the role of the gut–brain axis in the pathogenesis of obesity [ 3 ]. On the one hand, the brain signals to the gut via efferent vagal and neuroendocrine pathways [ 4 ], and on the other hand, peptide hormones act as signaling molecules [ 5 ], triggering autonomic reflexes to regulate appetite, energy, and glucose homeostasis [ 6 ].…”

Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice

“…Mimicking the native physiology of INSL5-RXFP4 via Di recapitulated these results, whereas chemogenetic cell activation via Dq suppressed HFD and HPM intake. Selective chemogenetic activation of Rxfp4 -expressing cells in the VMH alone (targeted via rAAV-Dq) also suppressed HFD and HPM intake, reflecting their position in brain circuits implicated in homeostatic and hedonic regulation of food intake(20). Ablation of the VMH Rxfp4 -positive cell population resulted in lower HFD consumption and body weight, mirroring the phenotype of global Rxfp4 knockout mice (4) and supporting the conclusion that Rxfp4 neurons in the VMH play a role in the physiological drive to consume highly palatable foods.…”

Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice

“…Mimicking the native physiology of INSL5-RXFP4 via Di recapitulated these results, whereas chemogenetic cell activation via Dq suppressed HFD and HPM intake. Selective chemogenetic activation of Rxfp4 -expressing cells in the VMH alone (targeted via Cre-dependent rAAV-Dq) also suppressed HFD and HPM intake, reflecting their position in brain circuits implicated in homeostatic and hedonic regulation of food intake [ 21 ]. Ablation of this population further demonstrated the importance of these neurones in governing long-term feeding behaviour.…”