Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity.

Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily -conserved secretory protein containing seven-and-a-half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases. In the central nervous system, PGRN is highly expressed in microglia. To investigate the role of microglia-derived PGRN in metabolism regulation, we established a mouse model with a microglia-specific deletion of the Grn gene, that encodes PGRN. Mice with microglia-specific Grn gene depletion displayed dietdependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn gene depletion produced adverse outcomes like fasting hyperglycemia and aberrant activation of hypothalamic microglia. However, when fed a high fat diet (HFD), these mice exhibited beneficial effects, including less obesity, glucose dysregulation, and hypothalamic inflammation. These differing phenotypes appear linked to increased extracellular cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus during overnutrition. In support of this, inhibiting PGRN cleavage attenuated HFD-induced hypothalamic inflammation and obesity progression. Our results suggest that the extracellular cleavage of microglia-derived PGRN plays a significant role in promoting hypothalamic inflammation and obesity during periods of overnutrition. Therefore, therapies that inhibit PGRN cleavage may be beneficial for combating dietinduced obesity.

Validation of the Finite Element Model versus Biomechanical Assessments of Dental Implants and Total Knee Replacements.

Computer modeling and simulation (CM&S) technology is widely used in the medical device industry due to its advantages such as reducing testing time and costs. However, the developer's parameter settings during the modeling and simulation process can have a significant impact on the results. This study developed a test model for the rotational shear strength of dental implants and the constraint force of total knee replacements based on CM&S technology and proposes ideal parameters to ensure reliability. For dental implants, the load area and sliding contact conditions were considered, and for total knee replacements, the friction coefficient, medial-lateral displacement, valgus-varus rotation, and elastic modulus were considered. By comparing the simulation results and mechanical tests, boundary conditions with an error rate of less than 1.5% were selected. When a jig (gripper and collector) was applied with the same boundary conditions, an error rate of 48~22% occurred; otherwise, it was confirmed that the error rate was within 10~0.2%. The FE model was verified with an error of 2.49 to 3% compared to the mechanical test. The friction coefficient variable had the greatest influence on the results, accounting for 10 to 13%, and it was confirmed that valgus-varus rotation had a greater influence on the results than medial-lateral displacement. Relatively, the elastic modulus of the insert had the least effect on the results. These research results are expected to make CM&S techniques useful as a medical device digital development tool (M3DT) in the development of total knee replacements and dental implants.

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. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+-SIRT-FOXO1-melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT-hypothalamic NAD+-FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.