Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism

Abstract

The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.

Hypothalamic inflammation in metabolic disorders and aging

“…Apart from the different hyperglycemic mice models, the direct administration of glucose into the mouse third ventricle has shown a significant increase in the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity in the hypothalamus [20]. In line with this, other studies reported that direct intraperitoneal injection of glucose in rodents also increased hypothalamic Il-1α, Il-1β mRNA and prostaglandins (PG) level [3,88]. Additionally, in vitro studies have shown that primary cultures of microglia, astrocytes, or Muller glial cells exposed to high glucose conditions exhibited increased production of inflammatory cytokines and reactive oxygen species (ROS) via activation of inflammatory signaling pathways [28,[89][90][91].…”

“…Additionally, it employs an integrated neuroendocrine network to direct peripheral metabolic activities. Through these mechanisms, the hypothalamus acts as a metabolic center that controls a variety of functions, such as glucose and fat metabolism [3,4], nutrient sensing [5], food intake behavior [6], body temperature regulation [7], energy homeostasis [8], blood pressure (BP) regulation [9], and aging [10]. At the cellular level, these physiological functions are conducted by several groups of neurons located in the mediobasal hypothalamus (MBH), paraventricular nucleus (PVN), and lateral hypothalamus (LH), which regulate the controlled synthesis, release, and action of hypothalamic neuropeptides and neurotransmitters [11].…”

Prostaglandin PGE2 receptor EP4 regulates microglial phagocytosis and increases susceptibility to diet-induced obesity

“…A recent study reported an increase in PGE2 levels in the arcuate nucleus following high fat diet (HFD) feeding [9]. Interestingly, we found a near-significant increase in expression of the receptor EP4 (encoded by the gene, Ptger4) in isolated microglia but not whole hypothalamus from HFD-fed mice (Supplementary Fig.…”

“…A recent study implicated hypothalamic PGE2 in microglial activation and metabolic regulation during DIO [9]. Preventing the increase in ventromedial hypothalamic PGE2 during HFD feeding by targeted knock-down of an enzyme involved in the generation of prostaglandin precursor molecules reversed microgliosis and improved glucose tolerance on HFD [9].…”

“…PGE2 signals through four G protein-coupled receptors (EP1-4), the downstream effects of which vary across tissues and conditions [8]. While their role in DIO is unclear, PGE2 levels are elevated in the arcuate nucleus of HFD-fed mice [9], which could modulate microglial activity through the EP receptors. EP4 is highly expressed in microglia and generally serves to constrain the microglial response to inflammatory stimuli such as lipopolysaccharide (LPS) and beta amyloid plaque in rodent models of Alzheimer's Disease [10,11].…”