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Chronic intake of high-energy diets alters the physiological response to food and favors overconsumption. Feeding, especially of palatable food, leads to dopamine (DA) release in the Nucleus Accumbens (NAc, in the ventral striatum), prefrontal cortex (PFC) and dorsal striatum. The mesocortical (ventral tegmental area (VTA) projecting to NAc) DA system has been implicated in motivational drive and food seeking while the nigrostriatal DA (projections from the substantia nigra (SN) to the dorsal striatum) pathway plays a role in both food anticipatory behavior and reinforcement. In humans, hypersensitivity to food-associated reward may predispose to weight gain, however as obesity progresses deficit in reward signaling emerges. Individuals with obesity have reduced DRD2 availability in prefrontal brain regions compared to lean counterparts. 

Jiyoung S. Kim, Kevin C. Williams, Rebecca A. Kirkland, Ruth Schade, ... Claire B. de La Serre

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Current Issue

Increased α-HB links colorectal cancer and diabetes by potentiating NF-κB signaling

Xinyue Lv, Peipei Ding, Luying Li, Ling Li, ... Weiguo Hu

Increased α-HB links colorectal cancer and diabetes by potentiating NF-κB signaling

Sufficient evidence has linked many different types of cancers and T2D through shared risk factors; however, the underlying mechanisms are not fully understood. α-Hydroxybutyrate (α-HB), a byproduct metabolite increased in diabetes and cancer, including colorectal cancer (CRC), triggers lactate dehydrogenase A (LDHA) nuclear translocation. Nuclear LDHA markedly extends NF-κB nuclear retention by interacting with phosphorylated p65, leading to an increase in TNF-α production, impaired insulin secretion and the exacerbation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC and high-fat diet (HFD)-induced type 2 diabetes. Furthermore, metformin interrupted this process by inhibiting the transcription of FOXM1 and c-MYC, the resultant downregulation of LDHA expression and α-HB-induced LDHA nuclear translocation. Thus, the results reveal the elevated α-HB level could be a novel shared risk factor of linking CRC, diabetes and the use of metformin treatment, as well as highlight the importance of preventing NF-κB activation for protecting against cancer and diabetes.

     

Articles in Press

Increased α-HB links colorectal cancer and diabetes by potentiating NF-κB signaling

Xinyue Lv, Peipei Ding, Luying Li, Ling Li, ... Weiguo Hu

Increased α-HB links colorectal cancer and diabetes by potentiating NF-κB signaling

Sufficient evidence has linked many different types of cancers and T2D through shared risk factors; however, the underlying mechanisms are not fully understood. α-Hydroxybutyrate (α-HB), a byproduct metabolite increased in diabetes and cancer, including colorectal cancer (CRC), triggers lactate dehydrogenase A (LDHA) nuclear translocation. Nuclear LDHA markedly extends NF-κB nuclear retention by interacting with phosphorylated p65, leading to an increase in TNF-α production, impaired insulin secretion and the exacerbation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC and high-fat diet (HFD)-induced type 2 diabetes. Furthermore, metformin interrupted this process by inhibiting the transcription of FOXM1 and c-MYC, the resultant downregulation of LDHA expression and α-HB-induced LDHA nuclear translocation. Thus, the results reveal the elevated α-HB level could be a novel shared risk factor of linking CRC, diabetes and the use of metformin treatment, as well as highlight the importance of preventing NF-κB activation for protecting against cancer and diabetes.

     

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