The brain control of appetite: Can an old dog teach us new tricks?
It is clear that the cause of obesity is a result of eating more than you burn. It is physics. What is more complex to answer is why some people eat more than others? Differences in our genetic make-up mean some of us are slightly more hungry all the time and so eat more than others. We now know that the genetics of body-weight, on which obesity sits on one end of the spectrum, is in actuality the genetics of appetite control. In contrast to the prevailing view, body-weight is not a choice. People who are obese are not bad or lazy; rather, they are fighting their biology.
The development of hunger
All mammals transition from breastfeeding to independent feeding during the lactation period. In humans and other mammals, this critical transition is important for later in life metabolic control and, consequently, for the development of many chronic conditions. Here, Dr. Dietrich will discuss the work of his lab studying the function of hypothalamic neurons involved in homeostatic control during the transition from breastfeeding to independent feeding. His work illuminates novel properties of hypothalamic neurons in early life, suggesting mechanisms by which early life events shape homeostatic regulation throughout the individual’s lifespan.
Estimation of current and future physiological states in insular cortex
Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. While human insular cortex (InsCtx) is implicated in interoception, the cellular and circuit mechanisms remain unclear. I will describe our recent work imaging mouse InsCtx neurons during two physiological deficiency states – hunger and thirst. InsCtx ongoing activity patterns reliably tracked the gradual return to homeostasis, but not changes in behavior. Accordingly, while artificial induction of hunger/thirst in sated mice via activation of specific hypothalamic neurons (AgRP/SFOGLUT) restored cue-evoked food/water-seeking, InsCtx ongoing activity continued to reflect physiological satiety. During natural hunger/thirst, food/water cues rapidly and transiently shifted InsCtx population activity to the future satiety-related pattern. During artificial hunger/thirst, food/water cues further shifted activity beyond the current satiety-related pattern. Together with circuit-mapping experiments, these findings suggest that InsCtx integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling upcoming ingestion of food/water, to compute a prediction of future physiological state.
Central representations of protein availability regulating appetite and body weight control
Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence support the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioural and neuroendocrine mechanisms underlying these adaptations are unclear and form the focus of our research.
Cortical estimation of current and future bodily states
Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. Human neuroimaging studies suggest insular cortex plays a central role in interoception, yet the cellular and circuit mechanisms of its involvement remain unclear. We developed a microprism-based cellular imaging approach to monitor insular cortex activity in behaving mice across different physiological need states. We combine this imaging approach with manipulations of peripheral physiology, circuit-mapping, cell type-specific and circuit-specific manipulation approaches to investigate the underlying circuit mechanisms. I will present our recent data investigating insular cortex activity during two physiological need states – hunger and thirst. These wereinduced naturally by caloric/fluid deficiency, or artificially by activation of specific hypothalamic “hunger neurons” and “thirst neurons”. We found that insular cortex ongoing activity faithfully represents current physiological state, independently of behavior or arousal levels. In contrast, transient responses to learned food- or water-predicting cues reflect a population-level “simulation” of future predicted satiety. Together with additional circuit-mapping and manipulation experiments, our findings suggest that insular cortex integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling availability of food/water. This way, insular cortex computes a prediction of future physiological state that can be used to guide behavioral choice.
Epigenetic Reprogramming of Taste by Diet
Diets rich in sugar, salt, and fat alter taste perception and food intake, leading to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of D. melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Importantly, half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.