The Pathophysiology of Defective Proteostasis in the Hypothalamus — From Obesity to Ageing

Hypothalamic dysfunction has emerged as an important mechanism involved in the development of obesity and its comorbidities, as well as in the process of ageing and age-related diseases, such as type 2 diabetes mellitus, hypertension and Alzheimer disease. In both obesity and ageing, inflammatory signalling is thought to coordinate many of the cellular events that lead to hypothalamic neuronal dysfunction. This process is triggered by the activation of signalling via the toll-like receptor 4 pathway and endoplasmic reticulum stress, which in turn results in intracellular inflammatory signalling. However, the process that connects inflammation with neuronal dysfunction is complex and includes several regulatory mechanisms that ultimately control the homeostasis of intracellular proteins and organelles (also known as 'proteostasis'). This Review discusses the evidence for the key role of proteostasis in the control of hypothalamic neurons and the involvement of this process in regulating whole-body energy homeostasis and lifespan.

Key points

• Specialized neurons of the hypothalamus control caloric intake and energy expenditure in response to hormonal, nutritional and neural signals that reflect the energy stores in the body
• Malfunction of the hypothalamus occurs in obesity and ageing, which leads to an imbalance between caloric intake and energy expenditure resulting in positive energy balance and reduced lifespan
• The excessive consumption of certain nutrients and ageing affect different aspects of proteostasis in selected neurons of the hypothalamus, contributing to neuronal dysfunction in obesity and ageing
• Inflammation is one of the most important outcomes of disturbed proteostasis to occur in the hypothalamus during obesity and ageing
• Several genetic and pharmacological approaches used to correct the defects of proteostasis and reduce inflammation have proven effective in reducing obesity and increasing lifespan in experimental models

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Figure 1: Control of energy balance and lifespan by the hypothalamic network. Neurons of the
medium hypothalamus respond to systemic signals of whole-body energy status. Blood levels of
insulin fluctuate acutely in response to carbohydrates present in food and chronically in response
to increased adiposity.

Source: Nature Reviews Endocrinology