The onset of type II diabetes increases the heart’s susceptibility to oxidative damage because of the associated inflammation and diminished antioxidant response. Transcription factor NF-κB initiates inflammation while Nrf2 controls antioxidant defense. Current evidence suggests crosstalk between these transcription factors that may become dysregulated during type II diabetes mellitus (T2DM) manifestation. The objective of this study was to examine the dynamic changes that occur in both transcription factors and target genes during the progression of T2DM in the heart. Novel UC Davis T2DM (UCD-T2DM) rats at the following states were utilized: (1) lean, control Sprague-Dawley (SD; n = 7), (2) insulin-resistant pre-diabetic UCD-T2DM (Pre; n = 9), (3) 2-week recently diabetic UCD-T2DM (2Wk; n = 9), (4) 3-month diabetic UCD-T2DM (3Mo; n = 14), and (5) 6-month diabetic UCD-T2DM (6Mo; n = 9). NF-κB acetylation increased 2-fold in 3Mo and 6Mo diabetic animals compared to SD and Pre animals. Nox4 protein increased 4-fold by 6Mo compared to SD. Nrf2 translocation increased 82% in Pre compared to SD but fell 47% in 6Mo animals. GCLM protein fell 35% in 6Mo animals compared to Pre. Hmox1 mRNA decreased 45% in 6Mo animals compared to SD. These data suggest that during the progression of T2DM, NF-κB related genes increase while Nrf2 genes are suppressed or unchanged, perpetuating inflammation and a lesser ability to handle an oxidant burden altering the heart’s redox state. Collectively, these changes likely contribute to the diabetes-associated cardiovascular complications.

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world’s population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1β) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.

Estrogen depletion in rodents and humans leads to inactivity, unhealthy fat accumulation, and diabetes ^1,2 , underscoring the conserved metabolic benefits of estrogen that inevitably decline with aging. In rodents, the preovulatory surge in 17β-estradiol (E2) temporarily allows energy expenditure to outpace energy intake, thus coordinating increased physical activity with peak sexual receptivity. To investigate how estrogen rebalances energy allocation in females, we examine estrogen receptor alpha (ERα) signaling in the ventrolateral ventromedial hypothalamic nucleus (VMHvl) ^3–7 . We uncover a small population of VMHvl ^ERα neurons expressing the melanocortin-4 receptor (MC4R) that integrates estrogen and melanocortin signals and projects to arousal centers in the hippocampus and hindbrain, enabling bursts of physical activity. ERα recruitment to the Mc4r gene promotes upregulation of Mc4r in VMHvl neurons during the preovulatory surge or following E2 treatment. We leveraged three models to stimulate VMHvl ^MC4R neurons, restore MC4R signaling in the VMHvl of hyperphagic MC4R null females, or increase Mc4r levels in the VMHvl by CRISPR-mediated activation. All models increase spontaneous activity, whereas silencing VMHvl ^MC4R neurons blunts normal activity. Direct activation of the VMHvl ^MC4R node overrides the inactivity and hypometabolism following hormone depletion. These data extend the impact of MC4R signaling – the most common cause of monogenic human obesity ⁸ – beyond the regulation of food intake. Our findings also rationalize reported sex differences in melanocortin signaling, including the greater disease severity of MC4R insufficiency in women ⁹ . The hormone-dependent node identified here illuminates the power of estrogen in motivating behavior during the female reproductive cycle and for maintaining an active lifestyle.