Abstract

 Adipose tissue and the brain are linked by dense neuroendocrine circuits that continuously coordinate appetite, 
energy expenditure, thermogenesis and glucose–lipid handling. This bidirectional “brain–fat axis” uses 
sympathetic and sensory nerves, together with circulating adipokines and gut-derived signals, to match fuel 
availability with storage and oxidation. In obesity, this communication progressively fails. Hypothalamic and 
brainstem networks that normally integrate leptin, insulin and nutrient cues become inflamed and resistant; 
sympathetic and sensory innervation of white and brown adipose tissue (WAT, BAT) is remodeled; and adipose
derived endocrine and immune signals feed back to further impair central control. The result is a self-reinforcing 
state of “diabesity,” where chronic positive energy balance, adipose dysfunction and type 2 diabetes (T2D) 
become tightly coupled.This review frames diabesity as a disorder of neuro–adipose signaling. First, we outline 
the anatomical and molecular architecture of brain–adipose circuits, emphasizing sympathetic efferents, 
emerging roles of PIEZO2-positive sensory afferents and key adipokine pathways. We then summarize how 
hypothalamic and brainstem nuclei use these channels to regulate lipolysis, adipogenesis, browning and 
thermogenesis in WAT and BAT. Next, we examine how obesogenic diets, chronic overnutrition and stress 
trigger hypothalamic inflammation, leptin and insulin resistance, and degeneration or functional impairment of 
adipose innervation. These changes uncouple caloric intake from expenditure and disrupt adipose endocrine 
outputs, promoting ectopic lipid deposition, insulin resistance and β-cell stress. Finally, we discuss emerging 
strategies to restore brain–adipose communication, including weight loss, structured sleep and circadian 
alignment, pharmacologic leptin and GLP-1–based therapies, and experimental neuromodulation of sympathetic 
outflow or adipose sensory circuits. We highlight open questions around human adipose innervation, sex- and 
depot-specific neuro–adipose wiring, and how to integrate neurobiological measures into precision care for 
obesity-related T2D.