People completely lacking body fat (lipodystrophy/lipoatrophy) and those with severe obesity both show profound metabolic and other health issues. Regulating levels of body fat somewhere between these limits would, therefore, appear to be adaptive. Two different models might be contemplated. More traditional is a set point (SP) where the levels are regulated around a fixed level. Alternatively, dual-intervention point (DIP) is a system that tolerates fairly wide variation but is activated when critically high or low levels are breached. The DIP system seems to fit our experience much better than an SP, and models suggest that it is more likely to have evolved. A DIP system may have evolved because of two contrasting selection pressures. At the lower end, we may have been selected to avoid low levels of fat as a buffer against starvation, to avoid disease-induced anorexia, and to support reproduction. At the upper end, we may have been selected to avoid excess storage because of the elevated risks of predation. This upper limit of control seems to have malfunctioned because some of us deposit large fat stores, with important negative health effects. Why has evolution not protected us against this problem? One possibility is that the protective system slowly fell apart due to random mutations after we dramatically reduced the risk of being predated during our evolutionary history. By chance, it fell apart more in some people than others, and these people are now unable to effectively manage their weight in the face of the modern food glut. To understand the evolutionary context of obesity, it is important to separate the adaptive reason for storing some fat (i.e. the lower intervention point), from the nonadaptive reason for storing lots of fat (a broken upper intervention point). The DIP model has several consequences, showing how we understand the obesity problem and what happens when we attempt to treat it.
Low-density lipoprotein (LDL) is the main carrier of cholesterol and cholesteryl ester in circulation. High plasma levels of LDL cholesterol (LDL-C) are a major risk factor of atherosclerotic cardiovascular disease (ASCVD). LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD. Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy. Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments. Here, we review the most recent advances on LDL-C-lowering drugs, focusing on the mechanisms by which they act to reduce LDL-C levels. The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD. Special treatments for those with little or no LDL receptor function then follow. The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein, which are recently approved and still under investigation for LDL-C lowering, respectively, are also included. Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.
Brown adipose tissue (BAT) plays a key role in thermogenesis during acute cold exposure. However, it remains unclear how BAT is prepared to rapidly turn on thermogenic genes. Here, we show that damage-specific DNA binding protein 1 (DDB1) mediates the rapid transcription of thermogenic genes upon acute cold exposure. Adipose- or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes. These mice develop hypothermia when subjected to acute cold exposure at 4 ℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation. Mechanistically, DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b (P-TEFb) to release promoter-proximally paused RNA polymerase II (Pol II), thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure. Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.
Diabetic cardiomyopathy (DCM) is currently a progressive and nonstoppable complication in type 2 diabetic patients. Metabolic insults and insulin resistance are involved in its pathogenesis; however, the underlying mechanisms are still not clearly understood. Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM. A western diet induces the development of DCM through at least three phases in mice, among which an early phase depends on impaired Thr484-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) elicited by insulin resistance. Mutation of SERCA2a-Thr484 to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline. Importantly, this mutation blunts the early phase of DCM, but has no effect on disease progression in the following phases. Interestingly, impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr484 mutation inhibited processing of insulin receptor precursor through FURIN convertase, resulting in cardiac insulin resistance. Collectively, these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis, which may underlie the early pathogenesis of DCM. Our findings have therapeutic implications for early intervention of DCM.
Infertility is a global concern attributed to genetic defects, lifestyle, nutrition, and any other factors that affect the local metabolism and niche microenvironment of the reproductive system. 2-Oxoglutarate receptor 1 (OXGR1) is abundantly expressed in the testis; however, its cellular distribution and biological function of OXGR1 in the male reproductive system remain unclear. In the current study, we demonstrated that OXGR1 is primarily expressed in epididymal smooth muscle cells (SMCs). Aging and heat stress significantly reduced OXGR1 expression in the epididymis. Using OXGR1 global knockout and epididymal-specific OXGR1 knockdown models, we revealed that OXGR1 is essential for epididymal sperm maturation and fluid acid–base balance. Supplementation of α-ketoglutaric acid (AKG), the endogenous ligand of OXGR1, effectively reversed epididymal sperm maturation disorders caused by aging and heat stress. Furthermore, in vitro studies showed that AKG markedly stimulated the release of instantaneous intracellular calcium from epididymal SMCs and substantially reduced the pHi value in the epididymal SMCs via OXGR1. Mechanistically, we discovered that AKG/OXGR1 considerably increased the expression of Na+/HCO3− cotransporter (NBCe1) mRNA in the epididymal SMCs, mediated by intracellular calcium signaling. The local AKG/OXGR1 system changed the epididymal fluid pH value and HCO3− concentration, thereby regulating sperm maturation via intracellular calcium signaling and NBCe1 mRNA expression. This study for the first time reveals the crucial role of OXGR1 in male fertility and sheds light on the applicability of metabolic intermediates in the nutritional intervention of reproduction.
Animals respond to mitochondrial perturbation by activating the mitochondrial unfolded protein response (UPRmt) to induce the transcription of mitochondrial stress response genes. In Caenorhabditis elegans, activation of UPRmt allows the animals to maintain organismal homeostasis, activate the innate immune response, and promote lifespan extension. Here, we show that splicing factors such as Precursor RNA processing 19 (PRP-19) are required for the induction of UPRmt in C. elegans. PRP-19 also modulates mitochondrial perturbation-induced innate immune response and lifespan extension. Knockdown of PRP-19 in mammalian cells suppresses UPRmt activation and disrupts the mitochondrial network. These findings reveal an evolutionarily conserved mechanism that maintains mitochondrial homeostasis and controls innate immunity and lifespan through splicing factors.