Predictive models of glucose control: roles for glucose‐sensing neurones

Abstract

The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure (e.g. sight, smell, taste, sound). This allows rapidly measurable sensory information (rather than slowly generated internal feedback signals, e.g. digested nutrients) to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely projecting hypothalamic neurones, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurones (i) are activated by sensory cues (e.g. taste, sound), (ii) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves, (iii) stimulate wakefulness and exploration via global brain projections and (iv) are glucose-inhibited. MCH neurones are (i) glucose-excited, (ii) innervate learning and reward centres to promote synaptic plasticity, learning and memory and (iii) are critical for learning associations useful for predictive control (e.g. using taste to predict nutrient value of food). This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurones may promote connections between the ‘fast’ senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurones may engage locomotion/exploration and coordinate the required fuel supply. Feedback inhibition of the latter neurones by glucose would ensure that glucose fluxes they stimulate (from liver, into muscle) are balanced. Estimating nutrient challenges from indirect sensory cues may become more difficult when the cues become complex and variable (e.g. like human foods today). Consequent errors of predictive glucose control may contribute to obesity and diabetes.

Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues

“…In addition, when optical stimulation of LH-MCH is combined with consumption of the non-caloric sweetener sucralose, MCH neuronal activation can substitute for glucose metabolism, reversing the normal preference for sucrose over sucralose and resulting in evoked dopamine responses in the striatum [51]. These findings suggest that MCH neurons form part of a complex network that integrates sensory, reward, and nutritional information from the periphery and central nervous system [51,52]. Based on this multifaceted role in the control of food intake, MCH neurons may function within a framework of allostasis [53], in which, through learning, animals come to anticipate their needs rather than simply reacting to them.…”

“…Based on this multifaceted role in the control of food intake, MCH neurons may function within a framework of allostasis [53], in which, through learning, animals come to anticipate their needs rather than simply reacting to them. For example, MCH may respond to sucrose-associated CSs leading to the release of insulin [48,49,52] in anticipation of glucose consumption, enhancing the efficiency of glucose metabolism [53]. It is tempting to speculate, however, that this efficient design for predictive regulation [52,53] may also lead to vulnerabilities to other mechanisms of learning that influence food intake such as CPF.…”

“…For example, MCH may respond to sucrose-associated CSs leading to the release of insulin [48,49,52] in anticipation of glucose consumption, enhancing the efficiency of glucose metabolism [53]. It is tempting to speculate, however, that this efficient design for predictive regulation [52,53] may also lead to vulnerabilities to other mechanisms of learning that influence food intake such as CPF. Future studies using foods of varying degrees of nutrition and palatability, along with specific targeting of MCH within the central and enteric nervous systems, will be informative for elucidating the complex role played by this neuropeptide on both the regulation and dysregulation of appetite control.…”

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

“…Olfactory dysfunction in narcolepsy has been reported to be reversed by intranasal orexin A (hypocretin 1) [63]. Animal studies have observed that orexin neurons are glucose-sensing, being inhibited by glucose [64]; thus, hyperglycaemia in people with diabetes may affect olfactory function through actions on orexin neurons in the lateral hypothalamus. Melanin concentrating hormone neurons, whose cell bodies are also located in the lateral hypothalamus, are glucose-excited and have been observed to have a potential role in olfactory function.…”

New concepts in microvascular function and metabolic diseases: importance of cephalic phase of insulin response

“…41 Rather than slowly generated, internal feedback signals, such as digested nutrients, allow rapidly measurable sensory information to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/ absorption. 42 Cephalic phase secretions of the gastrointestinal tract are initiated by activated vagal motor neurons 41 and include both exocrine secretions, such as saliva, gastric acid, and pancreatic enzymes, and endocrine hormones, such as gastrin, insulin, pancreatic polypeptide, and glucagon, among others. 40,43 When a meal is directly administered into the stomach, trespassing sensorial receptors, the early phase of digestion does not occur, corroborating that the sense of sight and smell stimulation is physiologically crucial to release of aforementioned substances and primary organic responses to initiate digestion.…”