Intestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids.http://deepblue.lib.umich.edu/bitstream/2027.42/169579/2/s41467-021-24914-y.pdfAccepted versio

Are elevated systemic bile acids involved in the pathophysiology of sarcopenia and liver injury following gastric bypass?

Bariatric surgery is currently the most effective treatment for sustained weight loss in severe obesity. However, recent data describe the development of liver damage and in particular massive steatosis and cholangitis in some patients, for which certain pathophysiological mechanisms are suggested such as bacterial overgrowth, malabsorption or sarcopenia. We describe the case of a patient presenting with a new liver dysfunction 6 years after a gastric bypass. The work-up revealed sarcopenic obesity characterised by low muscle mass and low muscle function as well as elevated fasting bile acids, severe liver steatosis and cholangitis. The pathophysiology of this disease is complex and multifactorial but could include bile acid toxicity. Bile acids are increased in cases of liver steatosis, but also in cases of gastric bypass and malnutrition. In our opinion, they may contribute to the loss of muscle mass and the vicious circle observed in this situation. Treatment with enteral feeding, intravenous albumin supplementation and diuretics reversed the liver dysfunction and the patient was discharged from hospital

Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia

Elevation of glucagon levels and increase in α-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and α-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2 ). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of α-cell proliferation, cell size, and mass expansion. Hyperglucagonemia in αTSC2 was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in αTSC2 mice was characterized by reduced expression of the glucagon receptor (GCGR), PEPCK, and genes involved in amino acid metabolism and urea production. Glucagon resistance in αTSC2 mice was associated with improved glucose levels in streptozotocin-induced β-cell destruction and high-fat diet-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver

The Role of Mediobasal Hypothalamic PACAP in the Control of Body Weight and Metabolism

Body energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus.This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAV(Cre)) injections to ablate Adcyapl (gene coding for PACAP) in mice (Adcyap1(MBH)KO mice). Adcyap1(MBH)KO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1(MBH)KO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis.While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1(MBH)KO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis

The Role of Elevated Branched-Chain Amino Acids in the Effects of Vertical Sleeve Gastrectomy to Reduce Weight and Improve Glucose Regulation.

Elevated levels of branched-chain amino acids (BCAAs) and their metabolites are strongly positively associated with obesity, insulin resistance, and type 2 diabetes. Bariatric surgery is among the best treatments for weight loss and associated morbidities. Clinical studies have reported that bariatric surgery decreases the circulating levels of BCAAs. The objective of this study was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements of sustained weight loss and improved glucose tolerance after vertical sleeve gastrectomy (VSG). We find that, as in humans, circulating BCAAs are significantly lower in VSG rats and mice. To increase circulating BCAAs, we tested mice with either increased dietary intake of BCAAs or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C (Pp2cm). Our results show that a decrease in circulating BCAAs is not necessary for sustained body weight loss and improved glucose tolerance after VSG

The Role of Elevated Branched-Chain Amino Acids in the Effects of Vertical Sleeve Gastrectomy to Reduce Weight and Improve Glucose Regulation.

Elevated levels of branched-chain amino acids (BCAAs) and their metabolites are strongly positively associated with obesity, insulin resistance, and type 2 diabetes. Bariatric surgery is among the best treatments for weight loss and associated morbidities. Clinical studies have reported that bariatric surgery decreases the circulating levels of BCAAs. The objective of this study was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements of sustained weight loss and improved glucose tolerance after vertical sleeve gastrectomy (VSG). We find that, as in humans, circulating BCAAs are significantly lower in VSG rats and mice. To increase circulating BCAAs, we tested mice with either increased dietary intake of BCAAs or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C (Pp2cm). Our results show that a decrease in circulating BCAAs is not necessary for sustained body weight loss and improved glucose tolerance after VSG