Hypothalamic astrocyte NAD salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.

Nicotinamide adenine dinucleotide (NAD) serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD).

Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure.

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT-NAD axis oscillates in a circadian manner and regulates the cellular clockwork.

Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism.

Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice.

Hypothalamic Macrophage Inducible Nitric Oxide Synthase Mediates Obesity-Associated Hypothalamic Inflammation.

Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages.

Regulation of energy balance by the hypothalamic lipoprotein lipase regulator Angptl3.

Hypothalamic lipid sensing is important for the maintenance of energy balance. Angiopoietin-like protein 3 (Angptl3) critically regulates the clearance of circulating lipids by inhibiting lipoprotein lipase (LPL). The current study demonstrated that Angptl3 is highly expressed in the neurons of the mediobasal hypothalamus, an important area in brain lipid sensing.