Nabin Ghimire

Aging is characterized by a gradual decline in physiological functions, impaired cellular repair mechanisms, and increased disease susceptibility. Mitogen‐activated protein kinase phosphatase‐2 (MKP‐2) regulates diverse biological functions, including regulation of infection, brain activity, nutrient metabolism, and cell‐cycle progression, but its role in senescence and adipose lipid metabolism in vivo remains unclear. Here, we investigated the effects of MKP‐2 deficiency on cellular senescence and adipose lipid composition in aged mice using targeted lipidomics. MKP‐2‐deficient mouse embryonic fibroblasts (MEFs) and epididymal white adipose tissue (EWAT) exhibited reduced premature senescence. Lipidomic analysis revealed increased hexosylceramides (HexCERs) and phosphatidylglycerols (PG), and decreased diacylglycerols (DGs) in adipose tissue. These lipid alterations were accompanied by preserved lamin B1, reduced p53 phosphorylation, p16, and PAI‐1, and increased JNK and Akt phosphorylation in EWAT. MKP‐2 deficiency was also associated with extended lifespan and enhanced insulin responsiveness. Together, these studies identify MKP‐2 as a potential regulator linking adipose lipid metabolism, stress‐responsive signaling, cellular senescence, and aging, with its loss promoting a metabolically resilient adipose state that may contribute to improved systemic health and lifespan.

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells.

The quadriceps angle, knowns as the Q-angle, is an anatomical feature of the human body that is still largely unknown and unstudied despite its initial discovery in the 1950s. The strength disparities between male and female athletes are largely determined by the Q-angle. In spite of a growing number of women participating in sports such as track, tennis, soccer, gymnastics, basketball, volleyball, swimming, and softball, studies investigating injuries in this group are scanty. Even though the Q-angle has been the subject of many studies carried out all over the world, a review of the literature regarding its effects on health and injury risk in female athletes has not yet been completed. The aim of this review is to examine the crucial role of the Q-angle in the biomechanics of the knee joint and its effect on performance and injury risk, particularly in female athletes. Furthermore, we highlight the greater likelihood of knee-related injuries seen in female athletes being caused by the Q-angle. Athletes, coaches, healthcare professionals, and athletic trainers can better comprehend and prepare for the benefits and drawbacks resulting from the Q-angle by familiarizing themselves with the research presented in this review.

The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2^−/− mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2^−/− mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2^−/− mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.

Obesity has reached global epidemic proportions and it affects the development of insulin resistance, type 2 diabetes, fatty liver disease and other metabolic diseases. Membrane lipids are important structural and signaling components of the cell membrane. Recent studies highlight their importance in lipid homeostasis and are implicated in the pathogenesis of fatty liver disease. Here, we discuss the numerous membrane lipid species and their metabolites including, phospholipids, sphingolipids and cholesterol, and how dysregulation of their composition and physiology contribute to the development of fatty liver disease. The development of new genetic and pharmacological mouse models has shed light on the role of lipid species on various mechanisms/pathways; these lipids impact many aspects of the pathophysiology of fatty liver disease and could potentially be targeted for the treatment of fatty liver disease.