The obesity epidemic in the face of homeostatic body weight regulation: What went wrong and how can it be fixed?

Abstract

Ever since the pioneering discoveries in the mid nineteen hundreds, the hypothalamus was recognized as a crucial component of the neural system controlling appetite and energy balance. The new wave of neuron-specific research tools has confirmed this key role of the hypothalamus and has delineated many other brain areas to be part of an expanded neural system sub serving these crucial functions. However, despite significant progress in defining this complex neural circuitry, many questions remain. One of the key questions is why the sophisticated body weight regulatory system is unable to prevent the rampant obesity epidemic we are experiencing. Why are pathologically obese body weight levels defended, and what can we do about it? Here we try to find answers to these questions by 1) reminding the reader that the neural controls of ingestive behavior have evolved in a demanding, restrictive environment and encompass much of the brain's major functions, far beyond the hypothalamus and brainstem, 2) hypothesizing that the current obesogenic environment impinges mainly on a critical pathway linking hypothalamic areas with the motivational and reward systems to produce uncompensated hyperphagia, and 3) proposing adequate strategies for prevention and treatment.

Keywords: AgRP; Food intake; Hypothalamus; Motivation; Reward.

Fig. 1.

By integrating external (red) and internal (blue) information, the brain (yellow) can regulate long-term body weight/adiposity flexibly and adaptively, to accommodate special circumstances (allostasis). Red dashed arrows represent sensory information to the brain. Green arrows represent behavioral, autonomic, and endocrine motor outflow from the brain. Reproduced with permission from [32].

Fig. 2.

The phases of ingestive behavior and its logistical tasks. Internal state and environmental signals interact to initiate ingestive behavior. In a natural restrictive environment, the procurement phase is the most complex and typically relies heavily on previous experience. It can involve extensive foraging, requiring considerable physical activity and energy, and it generates new memories for guiding future foraging behavior. The consumatory phase is typically less demanding when not contested. Besides rhythmic movements and autonomic support for ingestion and digestion, associative memories of the sensory qualities detected at all levels are formed, a process that continues after termination of the ingestive bout during digestion and absorption. The procurement, consummation, and termination phases are influenced by environmental factors. Short and long-term metabolic feedback signals lead to satiation and satiety. Hedonic feedback signals are derived from both sensory and postabsorptive consequences of food. Parts of the diagram are adapted from [28]. Blue boxes and arrows depicts metabolic, red boxes and arrows depict hedonic processes and signals.

Fig. 3.

Schematic diagram showing the intimate relationship between the classical homeostatic (light blue) and the hedonic (pink/red) neural systems controlling appetite, energy balance, and body weight. The classical homeostatic system (integrative energy sensor and response allocator) in the brainstem and hypothalamus is capable of sensing the internal milieu through circulating (broken light blue lines) and neural (solid light blue lines) signals and control energy intake and expenditure subconsciously (dark blue lines). The hedonic system senses signals from the environment, calculates emotional valence and reward value of potential goal objects through learning and memory, and can influence energy intake and expenditure through both conscious voluntary (red arrows) and unconscious (purple arrows) actions. Known interacting pathways are numbered, with blue numbers/pathways representing bottom-up modulation and red numbers/pathways representing top-down modulation. Bottom-up modulation: Circulating interoceptive signals have been shown to modulate external sensory inputs, various cortical areas, and other areas involved in learning and memory (pathway 1), as well as reward processing areas (pathway 2). Interoceptive signals mainly carried by vagal afferents reach vast cortical and subcortical areas, including the insular cortex (pathway 3). In addition, interoceptive information processed in the hypothalamus and brainstem reaches thalamus, hippocampus, and the reward system (pathways 3, 4, and 5). Specifically, there are orexin projections from the LH to the paraventricular nucleus of the hypothalamus and in turn to the nucleus accumbens (pathway 3), and to the ventral tegmental area (pathway 5). Top-down modulation: Taste, olfactory, and visual information can directly reach parts of the hypothalamus (pathway 6). Amygdala to lateral hypothalamic pathways mediate conditioned food intake (pathway 7). The hypothalamus receives massive inputs from many cortical and subcortical areas (pathway 8). The LH receives direct GABA-ergic input from the ventral striatum (pathway 9). Subconscious motor actions including autonomic nervous system outflow can originate from the striatum, the central amygdala (emotional motor system), and certain cortical areas, some of them passing through the periaqueductal gray (Pathways 10 and 11). Finally conscious willful motor actions can affect both food intake, food choice, and energy expenditure. Abbreviations: PAG, periaqueductal gray; VTA, ventral tegmental area; Vent. Pall, ventral pallidum; vmPFC, ventromedial prefrontal cortex.

Fig. 4.

Potential role of the basomedial hypothalamus and mesolimbic dopamine system in integrating classical homeostatic and hedonic controls of food intake and energy balance. AGRP and POMC neurons are key in sensing the nutritional state (blue arrows and boxes) and orchestrating adaptive anabolic and catabolic responses through behavioral, autonomic and endocrine actions (purple arrows). Notably, nutrient deficiency drives AGRP neuron activity and in turn the mesolimbic dopamine reward system to produce a sustained “wanting” of food. Environmental factors gain access to both AGRP neurons and the mesolimbic dopamine system through sensory channels and conditioned reward and energy expectancies (red boxes and arrows). We hypothesize that environmental pressure enhanced by easy availability, palatability, conditioned reward expectancy, and other factors further stimulate the AGRP-dopamine pathway, so that it is active even in the absence of a metabolic deficit.