Cooking shapes the structure and function of the gut microbiome.

Diet is a critical determinant of variation in gut microbial structure and function, outweighing even host genetics1-3. Numerous microbiome studies have compared diets with divergent ingredients1-5, but the everyday practice of cooking remains understudied. Here, we show that a plant diet served raw versus cooked reshapes the murine gut microbiome, with effects attributable to improvements in starch digestibility and degradation of plant-derived compounds. Shifts in the gut microbiota modulated host energy status, applied across multiple starch-rich plants, and were detectable in humans. Thus, diet-driven host-microbial interactions depend on the food as well as its form. Because cooking is human-specific, ubiquitous and ancient6,7, our results prompt the hypothesis that humans and our microbiomes co-evolved under unique cooking-related pressures.

Nutrient Excess and AMPK Downregulation in Incubated Skeletal Muscle and Muscle of Glucose Infused Rats.

We have previously shown that incubation for 1h with excess glucose or leucine causes insulin resistance in rat extensor digitorum longus (EDL) muscle by inhibiting AMP-activated protein kinase (AMPK). To examine the events that precede and follow these changes, studies were performed in rat EDL incubated with elevated levels of glucose or leucine for 30min-2h. Incubation in high glucose (25mM) or leucine (100µM) significantly diminished AMPK activity by 50% within 30min, with further decreases occurring at 1 and 2h. The initial decrease in activity at 30min coincided with a significant increase in muscle glycogen. The subsequent decreases at 1h were accompanied by phosphorylation of αAMPK at Ser485/491, and at 2h by decreased SIRT1 expression and increased PP2A activity, all of which have previously been shown to diminish AMPK activity. Glucose infusion in vivo, which caused several fold increases in plasma glucose and insulin, produced similar changes but with different timing. Thus, the initial decrease in AMPK activity observed at 3h was associated with changes in Ser485/491 phosphorylation and SIRT1 expression and increased PP2A activity was a later event. These findings suggest that both ex vivo and in vivo, multiple factors contribute to fuel-induced decreases in AMPK activity in skeletal muscle and the insulin resistance that accompanies it.

A fermentation product of Cordyceps sinensis increases whole-body insulin sensitivity in rats.

OBJECTIVE: CordyMax trade mark Cs-4 (Cs-4) is a standardized mycelial fermentation product of Cordyceps sinensis, a fungus that has been used for various pharmacologic, metabolic, and ergogenic purposes. The goal of this investigation was to determine the effects of oral Cs-4 administration on whole-body insulin sensitivity, skeletal muscle glucose transport, and endurance performance. DESIGN: We studied different indices of carbohydrate metabolism in rats that received Cs-4 orally at a dose of 2 g/kg of body weight daily for 30 days. RESULTS: C-peptide response observed during the oral glucose tolerance test (OGTT) after 10 days of treatment was significantly decreased in the Cs-4-treated group (Cs-4, 52,802 +/- 4,124 vs. control, 70,696 +/- 6309 pM x 120 min; p < 0.05). The integrated insulin area under the curve (53.3 +/- 4.9 ng/mL x 120 minutes) and the glucose-insulin index (6.6 +/- 0.6 units) obtained from the OGTT were significantly decreased (p < 0.01) in the Cs-4-treated group compared to their vehicle-treated counterparts (82.1 +/- 8.1 ng/mL x 120 minutes; 9.9 +/- 0.7 units) after 20 days of treatment. Neither integrated glucose area under the curve observed during either OGTT, basal- or insulin-stimulated 2-deoxyglucose transport nor skeletal muscle GLUT-4 concentrations were affected by Cs-4 treatment. In addition, swim time to exhaustion did not differ between groups in this animal model. CONCLUSION: We conclude that CordyMax Cs-4 may have potential beneficial effects by maintaining whole-body glucose disposal with a less pronounced increase in insulin secretion after a carbohydrate challenge, however, its effects on endurance performance remain questionable.

Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation?

It has long been known that excesses of glucose and branched chain amino acids, such as leucine, lead to insulin resistance in skeletal muscle. A recent study in incubated rat muscle suggests that both molecules may do so by virtue of their ability to downregulate the fuel sensing and signaling enzyme AMP-activated protein kinase (AMPK) and activate mTOR/p70S6 kinase (p70S6K) signaling. The results also demonstrated that inhibition of mTOR/p70S6K with rapamycin prevented the development of insulin resistance but had no effect on AMPK activity (Thr172 phosphorylation of its catalytic subunit). In contrast, activation of AMPK by both AICAR and α-lipoic acid led to the phosphorylation of specific molecules that diminished both mTOR/p70S6K signaling and insulin resistance. These findings suggest that downregulation of AMPK precedes mTOR/p70S6K activation in mediating glucose and leucine-induced insulin resistance, although the mechanism by which it does so remains to be determined. Also requiring study is how an excess of the two nutrients leads to AMPK downregulation.

GI262570, a peroxisome proliferator-activated receptor {gamma} agonist, changes electrolytes and water reabsorption from the distal nephron in rats.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients; however, these agents may cause fluid retention in susceptible individuals. Since PPARgamma is expressed selectively in distal nephron epithelium, we studied the mechanism of PPARgamma agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPARgamma agonist. GI262570 (20 mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570-induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570-induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaCalpha expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,K-ATPase system. This may be an important mechanism for PPARgamma agonist-induced fluid retention.