25 years ago, the future of treating obesity and diabetes focused on end organs known to be involved in energy balance and glucose regulation, including the brain, muscle, adipose tissue, and pancreas. Today, the most effective therapies are focused around the gut. This includes surgical options, such as vertical sleeve gastrectomy and Roux-en-Y gastric bypass, that can produce sustained weight loss

Alzheimer’s disease (AD) is associated with lower brain glucose metabolism. In this issue, Le Douce et al. (2020) show that this leads to insufficient astrocyte-dependent production of D-serine, co-agonist of synaptic NMDA receptors. Oral L-serine therapy rescues NMDA receptor hypofunction, plasticity, and cognition in an AD model, suggesting a new therapeutic strategy.

Engulfment of dying cells by phagocytes is essential to maintain tissue function and promote injury resolution and repair. This process, termed efferocytosis, requires persistent corpse engulfment and remains a poorly understood mechanism. Here, we preview findings from Yurdagul et al. (2020) that detail how continual efferocytosis is supported by metabolites derived from the dying cell itself.

The gut microbiota plays an important role for the absorption of nutrients and the maintenance of metabolism, potentially impacting the development of human metabolic disorders such as obesity and type 2 diabetes. In this issue of Cell Metabolism, Krisko et al. (2020) demonstrate that the gut microbiota regulates glucose homeostasis solely via hepatic gluconeogenesis and not via thermogenic adipose

The microbiome is well known to influence the immune response of the host. Song et al. now show that the microbiome modulates adaptive immunity in mice through formation of bile acid species acting on RORγ+ regulatory T cells via the Vitamin D Receptor, thereby lowering the vulnerability for chemically induced colitis.

The microbiota-gut-brain axis encompasses a bidirectional mode of communication between the microorganisms residing in our gut, and our brain function and behavior. The composition of the gut microbiota is subject to diurnal variation and is entrained by host circadian rhythms. In turn, a diverse microbiota is essential for optimal regulation of host circadian pathways. Disruption of the cyclical nature

The AMPK (AMP-activated protein kinase) and TOR (target-of-rapamycin) pathways are interlinked, opposing signaling pathways involved in sensing availability of nutrients and energy and regulation of cell growth. AMPK (Yin, or the “dark side”) is switched on by lack of energy or nutrients and inhibits cell growth, while TOR (Yang, or the “bright side”) is switched on by nutrient availability and promotes

Dietary methionine and its subsequent metabolism have profound effects on metabolic disease, cancer, and healthspan. In this issue of Cell Metabolism, Roy et al. (2020) report methionine as a nutritional factor for activated T cells that maintains H3K4 methylation and mediates functions that affect autoimmune disease.

The toxic effects of alcohol consumption are dependent upon its metabolism in the liver to downstream metabolites: acetaldehyde, acetate, and acetyl-CoA. Recently, in Nature, Mews et al. (2019) have discovered that acetyl-CoA derived from alcohol plays an important epigenetic role in regulating ethanol's effects on the brain through histone acetylation.

Neuromodulation is a promising new therapeutic avenue to treat chronic diseases. A paper that appeared recently in Nature Biotechnology (Guyot et al., 2019) now provides a roadmap for how to establish electrostimulation of nerves to delay or even prevent type 1 diabetes.

Deficiency of glucose, even under sufficient amino acid supply, turns off translation and promotes catabolic processes to aid cell survival. A recent report by Yoon et al. (2020) shows that glucose is required for the full activity of the leucyl-tRNA synthetase LARS1 and maintains mTORC1 function via LARS1 to enhance translation. Glucose starvation abolishes both effects via phosphorylation of LARS1

The beta (β)-cell mass formed during embryogenesis is amplified by cell replication during fetal and early postnatal development. Thereafter, β cells become functionally mature, and their mass is maintained by a low rate of replication. For those few β cells that replicate in adult life, it is not known how replication is initiated nor whether this occurs in a specialized subset of β cells. We capitalized

While reflecting upon the past five years of metabolic research, we asked leaders in the field what they envisioned the next five will hold and what challenges must be overcome. Here is an inspiring look onward to 2025, from leveraging technology and collaborations to advancing therapeutics and augmenting healthspan.

In this issue of Cell Metabolism, El Ouarrat et al. identify the Hippo signaling terminal effector TAZ as an endogenous negative regulator of PPARγ, a master transcriptional regulator of lipid metabolism and insulin sensitivity. Selective destruction of TAZ in adipocytes lowers inflammation and restores insulin sensitivity and glucose homeostasis.

Iron is essential for both the host and its resident microbes, resulting in competition under iron-deficient conditions. However, the molecular details underlying this competition are not fully understood. In this issue, Das et al. (2019) describe how a common gut commensal disrupts the host iron regulatory pathway to prevent uptake when iron is scarce.

Although confirmed as the primary lipophilic antioxidant molecule endogenously produced by cells, the non-mitochondrial pool of CoQ10's functional role is still well debated. Recently, both Bersuker et al. (2019) and Doll et al. (2019) have identified FSP1 as a novel CoQ10 plasma membrane oxidoreductase, protecting cells from glutathione-independent ferroptosis.

Genetic and pharmacological evidence causally demonstrate that the integrated stress response (ISR) is a central molecular switch for long-term memory formation across different species. Zhu et al. (2019) recently demonstrated that persistent activation of the ISR could explain the long-term memory and synaptic plasticity deficits in a mouse model of Down syndrome, the most common genetic cause of

Fatty liver disease (FLD), including its more severe pathologies, namely steatohepatitis, hepatocarcinoma, and cirrhosis, is the most common cause of chronic liver disease worldwide and is projected to become the leading cause of hepatocellular carcinoma and end-stage liver disease. FLD is heterogeneous with multiple etiologies and diverse histological phenotypes, so therapies will ultimately need

Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β cells that results in lifelong absolute insulin deficiency. For nearly a century, insulin replacement has been the only therapy for most people living with this disease. Recent advances in technology and our understanding of β cell development, glucose metabolism, and the underlying immune pathogenesis

Here, we explore the manipulation of immune cell metabolism as a strategy in target discovery and drug development for immune-mediated diseases. Comparing exploitation of metabolic pathways to kill tumor cells for cancer treatment with the reprogramming of immune cells to treat autoimmune diseases highlights differences that confer several advantages to the latter (including a more favorable therapeutic

Altered lipid metabolism is among the most prominent metabolic alterations in cancer. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Here, we summarize recent evidence

Conserved mechanisms of aging often illuminate the development of novel therapeutic interventions to delay aging and the onset of age-related diseases and functional decline. Recently in Cell Metabolism, Zivanovic et al. (2019) demonstrated a decline during aging of the protective H2S-dependent protein persulfidation across species and its reversal by targeted strategies.