Insulin resistance is an important feature of metabolic syndrome and a precursor of type 2 diabetes mellitus (T2DM). Overnutrition-induced obesity is a major risk factor for the development of insulin resistance and T2DM. The intake of macronutrients plays a key role in maintaining energy balance. The components of macronutrients distinctly regulate insulin sensitivity and glucose homeostasis. Precisely adjusting the beneficial food compound intake is important for the prevention of insulin resistance and T2DM. Here, we reviewed the effects of different components of macronutrients on insulin sensitivity and their underlying mechanisms, including fructose, dietary fiber, saturated and unsaturated fatty acids, and amino acids. Understanding the diet-gene interaction will help us to better uncover the molecular mechanisms of T2DM and promote the application of precision nutrition in practice by integrating multi-omics analysis.

Forkhead box protein O1 (Foxo1) is an insulin-suppressed transcription factor that governs multiple biological processes, including cell proliferation, apoptosis, autophagy, mitochondrial function, and energy metabolism. Over the past 25 years, Foxo1 has evolved from a liner insulin effector to a pleiotropic integrator of systemic metabolic stress during obesity and aging. Foxo1 integrates hormonal signals with energy balance and plays a central role in glucose and lipid metabolism, organ homeostasis, and immune responses. Given its pleiotropic functions, therapeutic targeting of Foxo1 pathway will require a nuanced, context-specific approach. Here, we reviewed key advances in Foxo1 studies over the past 25 years, including multi-hormonal control of Foxo1 activity, Foxo1-mediated inter-organ crosstalk, immune modulation, and contributions to aging-associated pathologies. Understanding the regulation of Foxo1 and its pleiotropic function across multiple tissues will advance insight into the pathogenesis of metabolic diseases and promote the translation potential of Foxo1 signaling manipulation for the treatment of metabolic disorders, including insulin resistance and type 2 diabetes.

Background: Endotoxemia is a severe inflammatory condition that is characterized by acute immune responses and oxidative stress; endotoxemia can further develop into a cytokine storm and sepsis leading to severe organ damage. Our recent studies revealed that the growth hormone secretagogue receptor (GHSR) regulates macrophage polarization in obesity- and aging-associated chronic inflammation. However, its role in acute inflammation during endotoxemia remains unclear. Methods: We subjected myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsr^f/f) to lipopolysaccharide (LPS)-induced endotoxemia in vivo and treated bone marrow-derived macrophages (BMDMs) with LPS in vitro. Subsequently, mouse survival rate and inflammatory signatures in the blood, peritoneal cavity, liver, and BMDM were assessed. In the ex vivo study, conditioned medium (CM) from BMDMs was applied to primary hepatocytes to assess how BMDM-derived CM influences hepatocyte inflammatory responses. Results: Myeloid-specific Ghsr knockout mice exhibited a significantly improved survival rate following LPS-induced endotoxemia, accompanied by reduced systemic inflammation, evident in the blood, peritoneal macrophages, and liver. In addition, Ghsr deficiency suppressed LPS-induced caspase-1 activation and pro-inflammatory cytokine secretion in macrophages. Consistent with these results, conditioned media from Ghsr-deficient BMDMs attenuated the inflammatory responses of primary hepatocytes. Mechanistically, LPS increased GHSR expression in BMDMs, and Ghsr-deficient BMDMs activated mitochondrial respiration and suppressed production of mitochondrial reactive oxygen species (ROS), resulting in downregulation of inflammatory activation of macrophages following LPS exposure. Conclusions: These data demonstrate that macrophage GHSR promotes systemic and tissue inflammation during endotoxemia by regulating mitochondria-associated macrophage polarization. The findings suggest that macrophage GHSR may represent a promising immunomodulatory target for acute inflammatory states, including endotoxemia and sepsis.