Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined, but they contribute to a host of other intracellular metabolic pathways, including ATP generation, nucleotide synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend on such pathways to acquire energy and biomass and to reprogram their metabolism

Bharath et al., 2020 report that CD4+ T lymphocytes from aged individuals exhibit defective mitochondrial autophagy, resulting in altered redox metabolism and upregulation of TH17 cytokines, which in turn may contribute to aging-associated chronic inflammation or “inflammaging.” Of note, the antiaging drug metformin reverses this autophagy defect and rejuvenates CD4+ T cell function.

The abundance of dietary sweeteners and overconsumption of fructose are widely thought to promote metabolic disease. In this issue of Cell Metabolism, Andres-Hernando et al. (2020) identify the liver as the major site of fructose metabolism-mediated metabolic dysfunction and identify a surprising role for intestinal fructose metabolism in driving fructose intake.

In a recent issue of Cell, Orthofer et al. (2020) present a body of data from mice, flies, and humans that suggest (1) a physiological role for Alk in the normal control of energy balance across several species and (2) a possible contribution of genetic variants in or near ALK to the variability of adiposity in humans, more specifically at its lower end.

Recent quantitative mass spectrometry and coexpression network analysis of postmortem human brain samples identified protein networks responsible for sugar metabolism and function of astrocytes and microglia are altered in Alzheimer’s disease and other types of neurodegenerative disorders. Boosting neuroglial function may represent a new strategy for containing neurodegeneration.

Recent studies have shown impressive cardiovascular health benefits in individuals treated with SGLT2 inhibitors (SGLT2i) regardless of diabetic status. The underlying mechanisms driving these benefits are not well understood. Recently in Circulation, Griffin et al. (2020) reported the first human study investigating the diuretic effect of empagliflozin.

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of

We are excited to announce that the Cell Metabolism Advisory Board has grown to better represent the metabolism community. We are honored to present these leaders as they share their perspectives. From taking unexpected journeys to pushing for a stronger future, they emphasize the indisputable value of curiosity, teamwork, diversity, and support.

In the era of a pandemic, networking opportunities have evaporated, and researchers are reinventing ways to connect with the community. It is our pleasure to build some of those connections, especially for young authors, by introducing you to eleven scientists whose work is featured in this issue. Here, they share their diverse and splendid journeys—from early concepts to the fruition of published

In this issue of Cell Metabolism, Pirinen et al. (2020) show that disruption in NAD+ homeostasis is a key component of the pathogenesis of mitochondrial myopathy in humans that can be targeted by the administration of the NAD+ precursor niacin, identifying NAD+ boosting as a potential treatment for this devastating disease.

Amphetamine (AMPH), mainly used in the treatment of attention deficit hyperactivity disorder and narcolepsy, has weight loss properties, although with detrimental cardiovascular effects. In this issue, Mahú et al. (2020) describe the effect of a new derivative of AMPH, “PEGyAMPH,” a brain-spared anti-obesity drug that alters sympathetic activity without cardiovascular side effects.

Itaconate is an immunometabolite with anti-inflammatory and anti-microbial properties. Riquelme et al. (2020) demonstrate that pathogenic Pseudomonas aeruginosa drives itaconate production by macrophages, which it then uses as a carbon source for biofilm formation, allowing it to persist during infection and suppress inflammation.

Mitochondrial fission is sustained through contact with several organelles, including the endoplasmic reticulum, lysosomes, and the actin cytoskeleton. Nagashima et al. (2020) now demonstrate that PI(4)P-containing Golgi-derived vesicles also modulate mitochondrial fission, driven by Arf1 and PI(4)KIIIβ activity, identifying a new organelle contact involved in maintaining mitochondrial homeostasis

The ketogenic diet is used to treat neurological and metabolic symptoms of disease, but the extent of its influences across organ systems remains unclear. Ang et al., 2020 reveal that ketone bodies induced by the diet inhibit specific bacteria of the gut microbiota and suppress pro-inflammatory T cells in the intestine.

While metabolism was initially thought to play a passive role in cell biology by generating ATP to meet bioenergetic demands, recent studies have identified critical roles for metabolism in the generation of new biomass and provision of obligate substrates for the epigenetic modification of histones and DNA. This review details how metabolites generated through glycolysis and the tricarboxylic acid

In this issue of Cell Metabolism, Herkenne et al. (2020) show that the mitochondrial fusion protein OPA1 promotes angiogenesis independent of its function in mitochondrial dynamics, identifying a key new therapeutic target to prevent vascular growth during development and tumor formation.

Cells within the islet of Langerhans are heterogeneous. Camunas-Soler et al. (2020) implement a patch-seq technique to collect both transcriptomic and electrophysiological data from the same cell. By doing so, they discover new genes that correlate with functional heterogeneity and find that shifts in these correlations indicate β cell compensation in type 2 diabetes.

It is unclear whether ex vivo bona fide distinct types of lymphocytes require the availability of different nutrients in the extracellular environment to support cell growth upon activation. Weisel et al. (2020) recently identified fatty acids as a predominant energy source for ex vivo bona fide germinal center B cell growth.

Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial—TAME (targeting aging by metformin). This review focuses on metformin’s mechanisms in attenuating hallmarks

In February, researchers convened in Banff, Canada, for the 2020 Keystone Symposium on Obesity and NAFLD. As the meeting wrapped up, we spoke with attendees, including key leaders, and they shared what was on the forefront of their minds—from the battle against NASH to emergent single-cell technologies.

Widespread technological advances have propelled human genetics into a “big data” era, in which genome-wide data from extremely large cohorts can be integrated with other “-omics” datasets from humans and model systems. Li et al. (2020) demonstrate the power of applying multiple computational analyses to publicly available data to prioritize the study of genes with novel trait associations.

In this issue of Cell Metabolism, Yang et al., 2020 report that serine is a source of mitochondrial NADH derived from one-carbon metabolism. Serine becomes a major source of NADH when cellular respiration is inhibited, and the un-utilized, accumulated NADH inhibits the TCA cycle and slows proliferation.

Covalent cysteine modification by reactive oxygen species (ROS) has been implicated in regulating diverse biological processes, yet global understanding of this modification has remained fragmentary. Developing new approaches for detecting cysteine modification, Xiao et al. (2020) recently charted a comprehensive map of cysteine oxidation across tissues and life stages.

Microglia exhibit differing functions and phenotypes depending on life stage and the context of health or disease. Recently, in Nature Neuroscience, Marschallinger et al. (2020) described a new state of microglia, namely “lipid-droplet-accumulating microglia” (LDAM), that contributes to neuronal inflammation and age-related neurodegeneration.

Lactate accumulation in tumors—a hallmark of the Warburg effect—has recently been shown to regulate cancer cell metabolism and survival through autocrine activation of GPR81. Now, Brown et al. (2020) demonstrate that lactate surprisingly also controls immune evasion through paracrine activation of GPR81 on stromal dendritic cells.

Defining functions for the full complement of proteins is a grand challenge in the post-genomic era and is essential for our understanding of basic biology and disease pathogenesis. In recent times, this endeavor has benefitted from a combination of modern large-scale and classical reductionist approaches-a process we refer to as "systems biochemistry"-that helps surmount traditional barriers to the

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