A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity

The Role of Oligofructose in Altering Small Intestinal Nutrient Sensing via the Gut Microbiota

Impairments in glucose homeostasis and insulin sensitivity in type II diabetic patients can be improved via manipulations to the gut microbiota. As such, therapies that alter the gut microbiota could serve as alternative treatments for diabetes and metabolic disorders. Treatment with the prebiotic oligofructose (OFS), a non-digestible carbohydrate known to beneficially alter the distal gut microbiota, decreases glucose production potentially via a gut-brain signal, although the exact mechanism remains unknown. As no studies have examined the effect of OFS on the small intestinal microbiota and given the recent evidence that the small intestinal microbiota can impact small intestinal nutrient sensing to regulate hepatic glucose production, we tested the hypothesis that OFS can restore the gut-brain-liver axis to decrease glucose production in response to a small intestinal nutrient infusion, which is abolished with high fat (HF)- feeding. We found that three-days of high fat feeding abolished the ability of small intestinal nutrients to decrease glucose production during euglycemic (basal insulin) pancreatic clamps. Both small intestinal carbohydrate and lipid nutrient sensing to decrease glucose production were restored in HF-fed rodents following two-day OFS supplementation. Microbiota swaps from HF+OFS treated donor rats into HF-fed recipient rats replicated the decrease in glucose production in response to carbohydrate or lipid small intestinal infusions. Lastly, we are the first to show that OFS treatment alters the small intestinal microbiota and that these shifts can impact small intestinal nutrient sensing to regulate glucose production

Fluid type influences acute hydration and muscle performance recovery in human subjects

Abstract Background Exercise and heat trigger dehydration and an increase in extracellular fluid osmolality, leading to deficits in exercise performance and thermoregulation. Evidence from previous studies supports the potential for deep-ocean mineral water to improve recovery of exercise performance post-exercise. We therefore wished to determine whether acute rehydration and muscle strength recovery was enhanced by deep-ocean mineral water following a dehydrating exercise, compared to a sports drink or mountain spring water. We hypothesized that muscle strength would decrease as a result of dehydrating exercise, and that recovery of muscle strength and hydration would depend on the type of rehydrating fluid. Methods Using a counterbalanced, crossover study design, female (n = 8) and male (n = 9) participants performed a dehydrating exercise protocol under heat stress until achieving 3% body mass loss. Participants rehydrated with either deep-ocean mineral water (Deep), mountain spring water (Spring), or a carbohydrate-based sports drink (Sports) at a volume equal to the volume of fluid loss. We measured relative hydration using salivary osmolality (Sosm) and muscle strength using peak torque from a leg extension maneuver. Results Sosm significantly increased (p < 0.0001) with loss of body mass during the dehydrating exercise protocol. Males took less time (90.0 ± 18.3 min; P < 0.0034) to reach 3% body mass loss when compared to females (127.1 ± 20.0 min). We used a mono-exponential model to fit the return of Sosm to baseline values during the rehydrating phase. Whether fitting stimulated or unstimulated Sosm, male and female participants receiving Deep as the hydrating fluid exhibited the most rapid return to baseline Sosm (p < 0.0001) regardless of the fit parameter. Males compared to females generated more peak torque (p = 0.0005) at baseline (308.3 ± 56.7 Nm vs 172.8 ± 40.8 Nm, respectively) and immediately following 3% body mass loss (276.3 ± 39.5 Nm vs 153.5 ± 35.9 Nm). Participants experienced a loss. We also identified a significant effect of rehydrating fluid and sex on post-rehydration peak torque (p < 0.0117). Conclusion We conclude that deep-ocean mineral water positively affected hydration recovery after dehydrating exercise, and that it may also be beneficial for muscle strength recovery, although this, as well as the influence of sex, needs to be further examined by future research. Trial registration clincialtrials.gov PRS, NCT02486224. Registered 08 June 2015