Central insulin action in energy and glucose homeostasis

Abstract

Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin's role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body's energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level. History and backgroundMore than 150 years ago, the French physiologist Claude Bernard identified the liver as a reservoir for glucose. Remarkably, he also showed in rabbits that "piqûre" (pricking) of the floor of the fourth ventricle of the brain resulted in glucosuria (1) and concluded that the CNS plays an essential role in the control of peripheral blood glucose levels. More recently, insulin signaling in neuronal cells has been shown to regulate life span, growth, reproduction, and energy homeostasis in primitive organisms such as Caenorhabditis elegans and Drosophila melanogaster (2, 3). The insulin/IGF-1 signal transduction pathway shows similar characteristics in C. elegans, D. melanogaster, rodents, and humans, pointing to an evolutionarily conserved mechanism (4). Signaling of the insulin/IGF-1 receptor homolog dauer formation-2 (DAF-2) via the class IA PI3K (AGE-1) pathway in C. elegans has been shown to control development, reproductive function, and longevity in response to environmental stimuli such as energy supply, a mechanism involving the forkhead-O transcription factor (FOXO) homolog 6). Likewise, the insulin receptor substrate (IRS) protein homolog CHICO in D. melanogaster regulates somatic growth, reproduction, and lipid metabolism (7).It has been shown that overexpression of D. melanogaster insulinlike peptides (dILPs) in the nervous system of fasted larvae suppresses the hunger-driven ingestion of food and that upregulation of D. melanogaster p70/S6 kinase (dS6K) activity in dILP neurosecretory cells leads to a diminished hunger response in fasted larvae (8). Furthermore, ablation of dILP neurons in the Drosophila brain was found to result in prolonged lifespan, reduced fertility, increased fasting glucose levels, increased storage of lipids and carbohydrates, and reduced tolerance to heat and cold (2, 9), clearly assigning neurosecretory cells a pivotal importance in the regulation of lifespan and fuel metabolism in D. melanogaster.The finding that insulin, like the adipocyte-derived hormone leptin, affects both neuropeptide expression in the hypothalamus and food intake has recently led to the appreciation of the brain as an insulin target tissue with regard t...

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

“…Insulin is also present in mammalian brain [21], and hypothalamic insulin actions cause inhibition of hepatic glucose production, which regulates fasting blood glucose levels [22,23]. We have previously reported that central administration of orexin reduces fasting blood glucose levels in mice, without changing serum insulin levels [24].…”

mTORC1 signaling in energy balance and metabolic disease

“…The latter is among the pathways known to mediate the appetite-suppressing actions of insulin and leptin in the hypothalamus. 25,26 In the presence of insulin, phosphorylation of Akt leads to inhibition of the tuberous sclerosis protein 2 (TSC2), which downregulates mTORC1 by inhibiting the GTPase Rheb (Ras homolog enriched in the brain). This therefore leads to mTORC1 activation.…”

“…48 As briefly mentioned before, insulin and leptin require an intact PI3K/Akt signaling in the ARC to reduce food intake. 25 The fact that mTORC1 is a downstream target of the PI3K/Akt pathway led us to hypothesize that hypothalamic mTORC1 signaling might be required for leptin-induced anorexia. Indeed, intracerebroventricular (i.c.v.)…”

Inducible and reversible gene silencing by stable integration of an shRNA-encoding lentivirus in transgenic rats

“…Impaired insulin signaling results in deregulation of glucose homeostasis and predisposes patients to obesity, vision impairment, and cardiovascular disease (18)(19)(20). To gain insight into the pathophysiology of insulin resistance and to exploit the advantages of the rat as a model organism, we used the recently developed lentiviral single-vector system to achieve an inducible and reversible knockdown of the insulin receptor (INSR).…”