Caloric restriction and intermittent fasting are emerging therapeutic strategies against obesity, insulin resistance and their complications. However, the effectors that drive this response are not completely defined. Here we identify arginase 2 (Arg2) as a fasting-induced hepatocyte factor that protects against hepatic and peripheral fat accumulation, hepatic inflammatory responses, and insulin and glucose intolerance in obese murine models. Arg2 is upregulated in fasting conditions and upon treatment with the hepatocyte glucose transporter inhibitor trehalose. Hepatocyte-specific Arg2 overexpression enhances basal thermogenesis, and protects from weight gain, insulin resistance, glucose intolerance, hepatic steatosis and hepatic inflammation in diabetic mouse models. Arg2 suppresses expression of the regulator of G-protein signalling (RGS) 16, and genetic RGS16 reconstitution reverses the effects of Arg2 overexpression. We conclude that hepatocyte Arg2 is a critical effector of the hepatic glucose fasting response and define a therapeutic target to mitigate the complications of obesity and non-alcoholic fatty liver disease.

Trehalose analogues designed to resist enzymatic hydrolysis are the first inhibitors of hypervirulence-associated trehalose metabolism in the pathogen Clostridioides difficile.

No abstract

Abstract Trehalose is a disaccharide that is the major sugar found in insect hemolymph fluid. Trehalose provides energy, and promotes growth, metamorphosis, stress recovery, chitin synthesis, and insect flight. The hydrolysis of trehalose is under the enzymatic control of the enzyme trehalase. Trehalase is critical to the role of trehalose in insect physiology, and is required for the regulation of metabolism and glucose generation. Trehalase inhibitors represent a novel class of insecticides that have not been fully developed. Here, we tested the ability of trehalose analogues to function as larvacides or adulticides in an important disease vector—Aedes aegypti. We show that validamycin A, but not 5-thiotrehalose, delays larval and pupal development and prevents flight of adult mosquitoes. Larval mosquitoes treated with validamycin A were hypoglycemic and pupae had increased levels of trehalose. Treatment also skewed the sex ratio toward male mosquitoes. These data reveal that validamycin A is a mosquito adulticide that can impair normal development of an important disease vector.

Trehalosamine (2-amino-2-deoxy-α,α-d-trehalose) is an aminoglycoside with antimicrobial activity against Mycobacterium tuberculosis, and it is also a versatile synthetic intermediate used to access imaging probes for mycobacteria. To overcome inefficient chemical synthesis approaches, we report a two-step chemoenzymatic synthesis of trehalosamine that features trehalose synthase (TreT)-catalyzed glycosylation as the key transformation. Soluble and recyclable immobilized forms of TreT were successfully employed. We demonstrate that chemoenzymatically synthesized trehalosamine can be elaborated to two complementary imaging probes, which label mycobacteria via distinct pathways.