Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Fasting- and ghrelin-induced food intake is regulated by NAMPT in the hypothalamus.

AIM: Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate-limiting enzyme in the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied. METHODS: We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet-induced obesity, by fasting and re-feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt, and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin-induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)-mediated FK866 administration. RESULTS: NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet-induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD+ , increased levels of ROS, and affected the expression of Agrp, Pomc and genes related to mitochondrial function. Finally, ICV-induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting- and ghrelin-induced increases in food intake. CONCLUSION: Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting- and ghrelin-induced food intake.

A randomised, controlled clinical study on total hip arthroplasty using 4 different bearings: results after 10 years.

PURPOSE: To compare 4 different bearings in total hip arthroplasty (THA) in a randomised controlled clinical study on clinical performance. METHODS: 393 patients with osteoarthritis of the hip or avascular necrosis were included and allocated to 1 of the head-and-cup couples zirconia-on-polyethylene (group A), metal-on-metal (group B), zirconia-on-polyethylene with the liner moulded into the shell (group C), or alumina-on-alumina (group D). In the individual case the surgeon could choose other implants if indicated. RESULTS: 299 patients were operated with the allocated prosthesis. The estimated cumulated prosthesis survival percentages and 95% confidence interval after 10 years were: group A 84.6 (75.8-93.4); group B 95.0 (89.5-100); group C 93.2 (86.7-99.7); group D 66.1 (54.5-77.7). The patients' physical function was significantly improved and remained equally good in all 4 groups, however slightly declining with ageing. The luxation rate was initially high, and equal between the groups, but was reduced by improving the surgical procedure introducing capsule repair by reinsertion of the short external hip rotators. CONCLUSIONS: The metal-on-metal or zirconia-on-polyethylene prostheses had high 10-year survival percentages. The longevity of these bearing couples by themselves was not related to the combination of materials. The zirconia-on-polyethylene prosthesis with the liner mounted peroperatively possibly exhibited cases of backside wear which the corresponding bearing couple with moulded polyethylene (Asian) did not. The alumina-on-alumina bearing performed poorly - it was redesigned after our study initiation and later withdrawn from the market.