Metabolic hormones mediate cognition

The brain controls energy regulation and feeding behaviour by detecting the status of energy stores and matching energy intake with expenditure (Luquet et al., 2019). Although comprising only a small fraction of our total body mass (∼2%), the brain has particularly high energy demands itself, using over 20% of the body’s glucose-derived energy (Howarth et al., 2012). Glucose metabolism is needed constantly for neuronal communication; energy from adenosine triphosphate (ATP) is needed to fire action potentials, restore post-synaptic potentials, and maintain ionic gradients, with neurons consuming 75%-80% of the energy in the brain (Harris et al., 2012, Howarth et al., 2012, Hyder et al., 2013). The brain cannot generate or store glucose itself, so it is reliant on glucose generated in the body from the food we eat, which can then be stored in astrocytes as glycogen to power metabolic processes. To maintain optimal brain function, energy metabolism must therefore be tightly regulated. Indeed, perturbations to glucose metabolism in the brain have been observed in dementias and neurodegenerative conditions including Alzheimer’s (Gaitán et al., 2019, Mosconi et al., 2009, Mosconi et al., 2008, Paz-Filho, 2016) and Parkinson’s diseases (Dunn et al., 2014, Meles et al., 2020).

Eating behaviour can be separated into homeostatic feeding – eating driven by internal hunger signals generated by endocrine energy-signalling molecules – and hedonic feeding, feeding in the absence of hunger, driven by neurobiologically regulated reward and learning processes in response to food-associated cues (for review see Reichelt et al., 2015). Thus, eating behaviours are based not only on hunger, but also on learning to anticipate the taste and digestive consequences of food intake. Both homeostatic and hedonic feeding are engaged by factors including food palatability and physiological states of starvation or satiation. Neuronal activity and connectivity adapt in response to energy intake and nutrient content, and activity in the neural circuits underlying eating behaviour and metabolism is influenced by neuroactive peptides, particularly circulating hormones (Rossi and Stuber, 2018).

Beyond their role in the control of eating behaviour and metabolism, metabolic hormones can trigger the synthesis or modification of proteins involved in synaptic transmission and neuroplasticity within feeding, memory, and learning centers in the brain. In particular, the metabolic hormones ghrelin, leptin, and insulin show similar properties to internal brain messengers including neurotrophic factors. Specifically, these hormones can influence and control cell proliferation and differentiation and modulate plasticity mechanisms, including synaptogenesis, dendritic arborisation, and cell survival (Åberg et al., 2003, Diano et al., 2006, McGregor et al., 2018, McGregor and Harvey, 2018, Nieto-Estévez et al., 2016, Rafalski and Brunet, 2011, Sato et al., 2006, Zhao et al., 2019). Areas of the brain such as the hypothalamus and hippocampus are rich in metabolic hormone receptors including growth hormone secretagogue receptor subtype 1a (GHSR1a), and insulin-like growth factor 1 receptor (IGF1R) (Åberg et al., 2003, Hornsby et al., 2016). Moreover, these signalling pathways support both neuronal energy metabolism and the neuronal processes that subserve cognition.

A wide range of metabolic hormones have been discussed in the control of eating since the 1950s (Mayer, 1953). Of these hormones, ghrelin, leptin, and insulin are most intensively investigated for their crucial link to food intake and energy expenditure/storage (Billes et al., 2012, Klok et al., 2007, Schwartz et al., 2000; Valassi et al., 2007), metabolic syndromes (Cai et al., 2021; Cui et al., 2017a; Gruzdeva et al., 2019, Ikezaki et al., 2002, Macor et al., 1997, Murray et al., 2014, Wiedmer et al., 2007), and more recently, their actions in the central nervous system (Paz-Filho, 2016, Spinelli et al., 2019, Stoyanova and Lutz, 2021). For this reason, in this review, we explore the role of eating behaviours and ghrelin, leptin, and insulin in the delicate regulation of neural plasticity and cognition. Additionally, we discuss how altered metabolic homeostasis as seen in obesity is a strong determinant of the severity of age-related cognitive decline and neurodegenerative disease.

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