In humans, the obese, insulin resistant condition has been noted to be coupled to decreased brain dopaminergic activity (either as a consequence of dopamine or dopamine receptor reduction) when assessed via PET scan with stable isotope labeled dopamine agonist methods (1-3). In metabolically healthy individuals, daily brain dopaminergic activity typically peaks during the early morning waking event that it actually participates in (4). Importantly, a plethora of data from multiple studies implicate important roles for changes in the circadian rhythm of central nervous system dopaminergic activity in the manifestation of seasonal metabolism (obese, insulin resistant vs lean, insulin sensitive states) across representative species of all the major vertebrate classes, spanning over 400 million years of evolution (reviewed in 5,6).   An endogenous programmed reduction in the natural circadian peak in brain dopaminergic activity facilitates the seasonal obese, insulin resistant state that evolved as a survival mechanism against seasonal low food (glucose) availability. This clock system also drives the reversal of the obese, insulin resistant state during seasons of ample food supply in large part via reinstatement of the circadian peak in central nervous system (CNS) dopaminergic activity. Seasonal changes in metabolic status among humans are well described in the scientific literature.

Environmental factors deriving from the westernized lifestyle of modern man that drive a sustained reduction in brain (circadian) dopaminergic activity include high fat, simple sugar diets, altered sleep/wake architecture, and psychosocial stress (3,7-10). Whether it is naturally occurring (seasonal expressions) or experimentally induced (e.g., high fat diet), a diminution of the natural circadian peak in brain dopaminergic activity (at daily waking) induces metabolic syndrome in a variety of tested animal model systems (5,6,11), also including in man (12,13). An important, but by no means only, site of circadian dopaminergic input signaling to CNS clock centers regulating peripheral fuel metabolism is the hypothalamic suprachiasmatic nucleus (SCN). Dopamine administration directly to the SCN of obese, insulin resistant animals at the time of day its activity peaks at the SCN in lean, insulin sensitive animals (daily waking time) reverses this dysmetabolism. This circadian dopaminergic effect is manifest via normalization of overactive Sympathetic Nervous System activity to the viscera and vasculature, of an overactive hypothalamic pituitary adrenal axis (raising and disrupting the normal circadian rhythm of plasma cortisol), and leptin resistance (5,6). Further studies in this regard indicate that systemic dopamine agonist treatment of metabolic syndrome resets towards normal (via the neuroendocrine axis) 1) aberrant hypothalamic glucose sensing (reducing post-meal hyperglycemia), 2) elevated hepatic lipogenesis (decreasing hyperlipidemia), 3) elevated adipose lipolysis (decreasing hyperFFAemia) and 4) hepatic and muscle insulin resistance (14-16).

Over the coming weeks this medical education notes series will review the basic and clinical science studies that delineate the central role of CNS dopamine-clock interactions in the regulation of cardiometabolic health and disease.