Treating Obesity Like a Tumor

Expanding adipose tissue in obesity requires a great deal of angiogenesis to support increasing volumes of tissue. A growing body of evidence indicates that inhibiting these blood vessels can result in substantial weight loss, and now this has been demonstrated in nonhuman primates

Mechanisms Underlying Weight Loss and Metabolic Improvements in Rodent Models of Bariatric Surgery

Obesity is a growing health risk with few successful treatment options and fewer still that target both obesity and obesity-associated comorbidities. Despite ongoing scientific efforts, the most effective treatment option to date was not developed from basic research but by surgeons observing outcomes in the clinic. Bariatric surgery is the most successful treatment for significant weight loss, resolution of type 2 diabetes and the prevention of future weight gain. Recent work with animal models has shed considerable light on the molecular underpinnings of the potent effects of these ‘metabolic’ surgical procedures. Here we review data from animal models and how these studies have evolved our understanding of the critical signalling systems that mediate the effects of bariatric surgery. These insights could lead to alternative therapies able to accomplish effects similar to bariatric surgery in a less invasive manner

Metabolic Effects of Bariatric Surgery in Mouse Models of Circadian Disruption

Background/Objectives: Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (for example, night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared with the non-disrupted population. However, it is unclear whether the obesity and obesity-related disorders associated with circadian disruption respond to therapeutic treatments as well as individuals with other types of obesity. Subjects/Methods: Here, we test the effectiveness of the commonly used bariatric surgical procedure, Vertical Sleeve Gastrectomy (VSG), in mouse models of genetic and environmental circadian disruption. Results: VSG led to a reduction in body weight and fat mass in both ClockΔ19 mutant and constant-light mouse models (PP\u3e0.05). Within circadian-disrupted models, VSG also led to improved glucose tolerance and lipid handling (P\u3c0.05). Conclusions: Together these data demonstrate that VSG is an effective treatment for the obesity associated with circadian disruption, and that the potent effects of bariatric surgery are orthogonal to circadian biology. However, as the effects of bariatric surgery are independent of circadian disruption, VSG cannot be considered a cure for circadian disruption. These data have important implications for circadian-disrupted obese patients. Moreover, these results reveal new information about the metabolic pathways governing the effects of bariatric surgery as well as of circadian disruption

The Role of Gut Adaptation in the Potent Effects of Multiple Bariatric Surgeries on Obesity and Diabetes

Bariatric surgical procedures such as vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most potent treatments available to produce sustained reductions in body weight and improvements in glucose regulation. While traditionally these effects are attributed to mechanical aspects of these procedures, such as restriction and malabsorption, a growing body of evidence from mouse models of these procedures points to physiological changes that mediate the potent effects of these surgeries. In particular, there are similar changes in gut hormone secretion, bile acid levels, and composition after both of these procedures. Moreover, loss of function of the nuclear bile acid receptor (FXR) greatly diminishes the effects of VSG. Both VSG and RYGB are linked to profound changes in the gut microbiome that also mediate at least some of these surgical effects. We hypothesize that surgical rearrangement of the gastrointestinal tract results in enteroplasticity caused by the high rate of nutrient presentation and altered pH in the small intestine that contribute to these physiological effects. Identifying the molecular underpinnings of these procedures provides new opportunities to understand the relationship of the gastrointestinal tract to obesity and diabetes as well as new therapeutic strategies to harness the effectiveness of surgery with less-invasive approaches

Metabolic Comparison of One-Anastomosis Gastric Bypass, Single-Anastomosis Duodenal-Switch, Roux-en-Y Gastric Bypass, and Vertical Sleeve Gastrectomy in Rat

Background One-anastomosis gastric bypass (OAGB) and single-anastomosis duodenal switch (SADS) have become increasingly popular weight loss strategies. However, data directly comparing the effectiveness of these procedures with Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) are limited. Objectives To examine the metabolic outcomes of OAGB, SADS, RYGB, and SG in a controlled rodent model. Setting Academic research laboratory, United States. Methods Surgeries were performed in diet-induced obese Long-Evans rats, and metabolic outcomes were monitored before and for 15 weeks after surgery. Results All bariatric procedures induced weight loss compared with sham that lasted throughout the course of the study. The highest percent fat loss occurred after OAGB and RYGB. All bariatric procedures had improved glucose dynamics associated with an increase in insulin (notably OAGB and SADS) and/or glucagon-like protein-1 secretion. Circulating cholesterol was reduced in OAGB, SG, and RYGB. OAGB and SG additionally decreased circulating triglycerides. Liver triglycerides were most profoundly reduced after OAGB and RYGB. Circulating iron levels were decreased in all surgical groups, associated with a decreased hematocrit value and increased reticulocyte count. The fecal microbiome communities of OAGB, SADS, and RYGB were significantly altered; however, SG exhibited no change in microbiome diversity or composition. Conclusions These data support the use of the rat for modeling bariatric surgical procedures and highlight the ability of the OAGB to meet or exceed the metabolic improvements of RYGB. These data point to the likelihood that each surgery accomplishes metabolic improvements through both overlapping and distinct mechanisms and warrants further research

Vertical sleeve gastrectomy improves ventilatory drive through a leptin-dependent mechanism

Obesity hypoventilation syndrome (OHS) is a serious disorder characterized by daytime hypercapnia, disordered breathing, and a reduction in chemosensitivity. Vertical sleeve gastrectomy (VSG), a bariatric surgical procedure resulting in weight loss and weight-independent improvements in glucose metabolism, has been observed to substantially improve sleep-disordered breathing. However, it is unclear if the ventilatory effects of VSG are secondary to weight loss or the marked change in metabolic physiology. Using preclinical mouse models, we found that VSG leads to an improvement in the hypercapnic ventilatory response (HCVR) and reductions in circulating leptin levels independent of reductions in body mass, fat mass, and caloric intake. In the absence of leptin, VSG continues to improve body mass, fat mass, and glucose tolerance in ob/ob mice but no longer affects HCVR. However, the HCVR of ob/ob mice can be returned to wild-type levels with leptin treatment. These data demonstrate that VSG improves chemosensitivity and ventilatory drive via a leptin-dependent mechanism. Clinically, these data downgrade the relative contribution of physical, mechanical load in the pathogenesis of OHS, and instead point to physiological components of obesity, including alterations in leptin signaling, as key drivers in OHS

Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight

Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei