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A genetic mouse model is used to reveal a two-pronged mechanism of fructose-induced de novo lipogenesis in the liver, in which fructose catabolism in hepatocytes provides a signal to promote lipogenesis, whereas fructose metabolism by the gut microbiota provides acetate as a substrate to feed lipogenesis.

Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods(1), and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease(2-4). Fructose intake triggers de novo lipogenesis in the liver(4-6), in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates(7). Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases(8). However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota(9), and this supplies lipogenic acetyl-CoA independently of ACLY(10). Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.

Sea-level histories during the two most recent deglacial-interglacial intervals show substantial differences(1-3) despite both periods undergoing similar changes in global mean temperature(4,5) and forcing from greenhouse gases(6). Although the last interglaciation (LIG) experienced stronger boreal summer insolation forcing than the present interglaciation(7), understanding why LIG global mean sea level may have been six to nine metres higher than today has proven particularly challenging(2). Extensive areas of polar ice sheets were grounded below sea level during both glacial and interglacial periods, with grounding lines and fringing ice shelves extending onto continental shelves(8). This suggests that oceanic forcing by subsurface warming may also have contributed to ice-sheet loss(9-12) analogous to ongoing changes in the Antarctic(13,14) and Greenland(15) ice sheets. Such forcing would have been especially effective during glacial periods, when the Atlantic Meridional Overturning Circulation (AMOC) experienced large variations on millennial timescales(16), with a reduction of the AMOC causing subsurface warming throughout much of the Atlantic basin(9,12,17). Here we show that greater subsurface warming induced by the longer period of reduced AMOC during the penultimate deglaciation can explain the more-rapid sea-level rise compared with the last deglaciation. This greater forcing also contributed to excess loss from the Greenland and Antarctic ice sheets during the LIG, causing global mean sea level to rise at least four metres above modern levels. When accounting for the combined influences of penultimate and LIG deglaciation on glacial isostatic adjustment, this excess loss of polar ice during the LIG can explain much of the relative sea level recorded by fossil coral reefs and speleothems at intermediate- and far-field sites.