Physiology of Energy Intake in the Weight‐Reduced State

Abstract

Physiological adaptations to intentional weight loss can facilitate weight regain. This review summarizes emerging findings on hypothalamic and brainstem circuitry in the regulation of body weight and identifies promising areas for research to improve therapeutic interventions for sustainable weight loss. There is good evidence that body weight is actively regulated in a homeostatic fashion similar to other physiological parameters. However, the defended level of body weight is not fixed but rather depends on environmental conditions and genetic background in an allostatic fashion. In an environment with plenty of easily available energy‐dense food and low levels of physical activity, prone individuals develop obesity. In a majority of individuals with obesity, body weight is strongly defended through counterregulatory mechanisms, such as hunger and hypometabolism, making weight loss challenging. Among the options for treatment or prevention of obesity, those directly changing the defended body weight would appear to be the most effective ones. There is strong evidence that the mediobasal hypothalamus is a master sensor of the metabolic state and an integrator of effector actions responsible for the defense of adequate body weight. However, other brain areas, such as the brainstem and limbic system, are also increasingly implicated in body weight defense mechanisms and may thus be additional targets for successful therapies.

New insights in the mechanisms of weight‐loss maintenance: Summary from a Pennington symposium

“…Understanding the physiology of the weight‐reduced state is a priority of leading scientific agencies, including the NIH. In 2019, NIDDK hosted a workshop discussing the physiology of the weight‐reduced state [5, 119–122] and shortly after, released a funding opportunity announcement (https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-19-017.html) aimed to elucidate the complex physiological underpinnings of WLM. In 2021, the Physiology of the Weight Reduced State (POWeRS) consortium was formed, including Columbia University, Drexel University, University of Pennsylvania, and Tufts University.…”

Novel Insights into the Physiology of Nutrient Sensing and Gut-Brain Communication in Surgical and Experimental Obesity Therapy

“…Historically, the mediobasal hypothalamus has been considered the main sensor of the metabolic state and the integrator of effector actions aiming at an optimal body weight [66]. However, the hindbrain and the limbic system are other key brain areas implicated in body weight-regulating mechanisms that serve as alternative targets for weight loss therapies [66].…”

Sensory spinal interoceptive pathways and energy balance regulation

“…Although prevention of obesity should be our priority, research has shifted to understand and prevent weight regain after dietary, pharmacological, and surgical interventions [ [4] , [5] , [6] , [7] , [8] ]. Because the elevated body weight in most patients with obesity is becoming their new, actively defended setpoint, weight regain should be considered as a normal physiological response to weight loss [ 6 , 9 ]. These powerful responses such as increased hunger and reduced metabolism lessen the effectiveness of most weight loss treatments unless they directly impact the elusive setpoint mechanism.…”