Blautia Coccoides is a Newly Identified Bacterium Increased by Leucine Deprivation and has a Novel Function in Improving Metabolic Disorders.

Gut microbiota is linked to human metabolic diseases. The previous work showed that leucine deprivation improved metabolic dysfunction, but whether leucine deprivation alters certain specific species of bacterium that brings these benefits remains unclear. Here, this work finds that leucine deprivation alters gut microbiota composition, which is sufficient and necessary for the metabolic improvements induced by leucine deprivation.

Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice.

An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect.

Leucine deprivation results in antidepressant effects via GCN2 in AgRP neurons.

Essential amino acids (EAAs) are crucial nutrients, whose levels change in rodents and patients with depression. However, how the levels of a single EAA affects depressive behaviors remains elusive. Here, we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice, it remarkably reverses the depression-like behaviors induced by chronic restraint stress (CRS).

Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB).

Impairment of gluconeogenesis is a key factor responsible for hyperglycemia in patients with type 2 diabetes. As an important member of the suppressors of cytokine signaling (SOCS) protein family, many physiological functions of cytokine-inducible SH2-containing protein (CISH) have been described; however, the role of hepatic CISH in gluconeogenesis is poorly understood. In the present study, we observed that hepatic CISH expression was reduced in fasted wild-type (WT) mice.

Amino acid sensor GCN2 promotes SARS-CoV-2 receptor ACE2 expression in response to amino acid deprivation.

Angiotensin-converting enzyme 2 (ACE2) has been identified as a primary receptor for severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2). Here, we investigated the expression regulation of ACE2 in enterocytes under amino acid deprivation conditions. In this study, we found that ACE2 expression was upregulated upon all or single essential amino acid deprivation in human colonic epithelial CCD841 cells.

Hepatokine ERAP1 Disturbs Skeletal Muscle Insulin Sensitivity Via Inhibiting USP33-Mediated ADRB2 Deubiquitination.

Chronic inflammation in liver induces insulin resistance systemically and in other tissues, including the skeletal muscle (SM); however, the underlying mechanisms remain largely unknown. RNA sequencing of primary hepatocytes from wild-type mice fed long-term high-fat diet (HFD), which have severe chronic inflammation and insulin resistance revealed that the expression of hepatokine endoplasmic reticulum aminopeptidase 1 (ERAP1) was upregulated by a HFD. Increased ERAP1 levels were also observed in interferon-γ-treated primary hepatocytes.

Intermittent Leucine Deprivation Produces Long-lasting Improvement in Insulin Sensitivity by Increasing Hepatic Gcn2 Expression.

Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended are unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles of treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after a control diet was resumed for 49 days) effect on improved whole-body and hepatic insulin sensitivity in mice, indicating the potential formation of metabolic memory.

Activation of GCN2 in macrophages promotes white adipose tissue browning and lipolysis under leucine deprivation.

We have previously shown that leucine deprivation stimulates browning and lipolysis in white adipose tissue (WAT), which helps to treat obesity. Adipose tissue macrophages (ATMs) significantly influence WAT browning and lipolysis. However, it is unclear whether ATMs are involved in leucine deprivation-induced browning and lipolysis in WAT; the associated signals remain to be elucidated.

Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling.

Objective: Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders.

Methods: We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice.

ATF4 Deficiency Promotes Intestinal Inflammation in Mice by Reducing Uptake of Glutamine and Expression of Antimicrobial Peptides.

Background & Aims: Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBDs) and mice with enterocolitis.

Methods: We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of the colon from 21 patients with active Crohn's disease (CD), 22 patients with active ulcerative colitis (UC), and 38 control individuals without IBD and of the ileum from 19 patients with active CD and 8 individuals without IBD in China.

Deletion of ATF4 in AgRP Neurons Promotes Fat Loss Mainly via Increasing Energy Expenditure.

Although many functions of activating transcription factor 4 (ATF4) are identified, a role of ATF4 in the hypothalamus in regulating energy homeostasis is unknown. Here, we generated adult-onset agouti-related peptide neuron-specific ATF4 knockout (AgRP-ATF4 KO) mice and found that these mice were lean, with improved insulin and leptin sensitivity and decreased hepatic lipid accumulation. Furthermore, AgRP-ATF4 KO mice showed reduced food intake and increased energy expenditure, mainly because of enhanced thermogenesis in brown adipose tissue.

BTG1 ameliorates liver steatosis by decreasing stearoyl-CoA desaturase 1 (SCD1) abundance and altering hepatic lipid metabolism.

Liver steatosis, a condition in which lipid accumulates in liver cells, is a leading cause of many liver diseases. The livers of patients with hepatocellular carcinoma, a cancer characterized by liver steatosis, have decreased abundance of the transcription cofactor BTG1 (B cell translocation gene 1). We showed that the livers of db/db mice, which are a genetic model of obesity, had decreased BTG1 mRNA and protein abundance.