Related Experiment Video
Updated: Jun 4, 2026
07:34
Quantitative Determination of De Novo Fatty Acid Synthesis in Brown Adipose Tissue Using Deuterium Oxide
Published on: May 12, 2023
Reductive death is averted by a conserved de novo lipogenic switch
Fasih M Ahsan1, Jen F Rotti2, Armen I Yerevanian3
1Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Molecular Cell
|June 2, 2026
Summary
Biguanides like metformin can cause toxicity by accumulating damaging reducing equivalents. This unexpected side effect requires de novo lipogenesis for defense, impacting health span and lifespan outcomes.
Area of Science:
- Biochemistry
- Gerontology
- Metabolic diseases
Background:
- Biguanides, such as metformin, are widely used oral hypoglycemic agents known to extend health span and lifespan.
- Metformin's safety is generally assumed, with toxicity only expected at very high doses.
Purpose of the Study:
- To investigate the unanticipated toxicity of biguanides.
- To identify the defense mechanisms against biguanide-induced toxicity.
- To explore the role of lipogenesis in mitigating these effects.
Main Methods:
- Investigated biguanide effects on reducing equivalents (NADPH, NADH, GSH) in various organisms.
- Assessed the role of de novo lipogenesis and fatty acid biosynthesis in response to biguanide treatment.
- Examined interventions that generate NADPH under conditions of impaired lipogenesis.
Main Results:
- Biguanide treatment leads to the accumulation of damaging reducing equivalents, specifically NADPH toxicity.
- Impaired de novo lipogenesis exacerbates NADPH toxicity, causing elevated NADH/GSH and accelerated death.
- De novo lipogenesis is crucial for preventing shortened survival during NADPH-generating interventions.
Conclusions:
- Biguanide toxicity arises from the accumulation of damaging reducing equivalents, challenging the assumption of their universal safety.
- De novo lipogenesis acts as a critical defense mechanism against biguanide-induced reductive stress.
- Fatty acid biosynthesis represents a potential therapeutic target for managing biguanide side effects and treating reductive stress-sensitive cancers.
Related Concept Videos
01:25Lipid Catabolism
Triglycerides serve as crucial long-term energy storage molecules in microorganisms, providing a dense source of metabolic energy. Their breakdown is mediated by lipases, which hydrolyze triglycerides into glycerol and free fatty acids. Each of these components follows distinct metabolic pathways, ultimately contributing to ATP synthesis and cellular energy homeostasis.Glycerol MetabolismGlycerol, released from triglyceride hydrolysis, is phosphorylated by glycerol kinase to form...
01:16Necrosis
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
01:24Overview of Lipid Metabolism
Lipid metabolism is a crucial process in the human body that involves the synthesis and degradation of lipids. This process is essential for energy production, cell membrane formation, and hormone production, among other functions.
Lipolysis: The Breakdown of Lipids:
Lipolysis is the process of breaking down lipids, particularly triglycerides, into glycerol and fatty acids. This process typically occurs in the adipose tissue and is triggered by various hormones, including glucagon and...
Lipolysis: The Breakdown of Lipids:
Lipolysis is the process of breaking down lipids, particularly triglycerides, into glycerol and fatty acids. This process typically occurs in the adipose tissue and is triggered by various hormones, including glucagon and...
01:23Tissue Renewal without Stem Cells
After cellular or tissue damage, the resident stem cells present in the human body can locally repair and regenerate the damaged tissue or organ. However, even though some tissues do not have stem cells, they can repair and regenerate with the help of pre-existing cells. For example, beta cells of the pancreas and hepatocytes of the liver can divide to renew and regenerate the tissue. Here, both cell division and cell death are well regulated by homeostasis.
However, failure of such a system...
However, failure of such a system...
01:30Overview of Cell Death
Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
01:29Biosynthesis of Lipids
Microbial membranes exhibit remarkable diversity in lipid composition, reflecting evolutionary adaptations to various environmental conditions. The three domains of life—Bacteria, Archaea, and Eukarya—synthesize membrane lipids through distinct biosynthetic pathways, leading to fundamental structural differences that impact membrane stability, function, and adaptability.Fatty Acid-Based Lipids in Bacteria and EukaryaBacteria and eukaryotes share a common fatty acid biosynthesis pathway, which...