Sex-based differences in insulin resistance.

Sexual dimorphism in energy metabolism is now established and suggested to affect many aspects of metabolic diseases and in particular diabetes and obesity. This is strongly related to sex-based differences in whole-body insulin resistance. Women are more insulin sensitive compared to men, but this metabolic advantage gradually disappears after menopause or when insulin resistance progresses to hyperglycemia and diabetes. In this narrative review, first, we describe the pathophysiology related to insulin resistance and then we present the epidemiological evidence as well as the important biological factors that play a crucial role in sexual dimorphism in insulin sensitivity. We focus particularly on the differences in body fat and muscle mass distribution and function, in inflammation and in sex hormones between males and females. Most importantly, we describe the significant mechanistic differences in insulin sensitivity as well as glucose and lipid metabolism in key metabolic organs: liver, white adipose tissue, and skeletal muscle. Finally, we present the sex-based differences in response to different interventions and discuss important open research questions.

Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases.

Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.

Activation of ß-adrenergic receptor signaling prevents glucocorticoid-induced obesity and adipose tissue dysfunction in male mice.

Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective ß3-adrenergic receptor (ß3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective ß3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective ß3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of ß3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease.NEW & NOTEWORTHY This preclinical study in mice shows that the ß3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and ß3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.

Bad to the Bone: The Effects of Therapeutic Glucocorticoids on Osteoblasts and Osteocytes.

Despite the continued development of specialized immunosuppressive therapies in the form of monoclonal antibodies, glucocorticoids remain a mainstay in the treatment of rheumatological and auto-inflammatory disorders. Therapeutic glucocorticoids are unmatched in the breadth of their immunosuppressive properties and deliver their anti-inflammatory effects at unparalleled speed. However, long-term exposure to therapeutic doses of glucocorticoids decreases bone mass and increases the risk of fractures - particularly in the spine - thus limiting their clinical use. Due to the abundant expression of glucocorticoid receptors across all skeletal cell populations and their respective progenitors, therapeutic glucocorticoids affect skeletal quality through a plethora of cellular targets and molecular mechanisms. However, recent evidence from rodent studies, supported by clinical data, highlights the considerable role of cells of the osteoblast lineage in the pathogenesis of glucocorticoid-induced osteoporosis: it is now appreciated that cells of the osteoblast lineage are key targets of therapeutic glucocorticoids and have an outsized role in mediating their undesirable skeletal effects. As part of this article, we review the molecular mechanisms underpinning the detrimental effects of supraphysiological levels of glucocorticoids on cells of the osteoblast lineage including osteocytes and highlight the clinical implications of recent discoveries in the field.

Cutting Edge: Homeostasis of Innate Lymphoid Cells Is Imbalanced in Psoriatic Arthritis.

Innate lymphoid cells (ILC) have a high potency for cytokine production independent of specific Ag stimulation. Imbalance of ILC subsets may influence cytokine production in humans and hence be associated with the development of inflammatory disease. Evidence for an imbalance of ILC homeostasis in human disease, however, is very limited to date. In this study we show that psoriatic arthritis (PsA), a severe disease of the joints depending on the activation of the IL-23/IL-17 pathway, is characterized by a skewed ILC homeostasis. Circulating ILC3s as potent source of IL-17/IL-22 were elevated in active PsA, whereas ILC2s, which produce proresolving cytokines, were decreased. The ILC2/ILC3 ratio was significantly correlated with clinical disease activity scores and the presence of imaging signs of joint inflammation and bone damage. Multivariable analysis showed that a high ILC2/ILC3 ratio is associated with remission in PsA, suggesting that specific alterations of ILC homeostasis control disease activity in PsA.