Compelling evidence supports the concepts that gut microbiota actively promotes weight gain and fat accumulation and sustains, indirectly, a condition of low-grade inflammation, thus enhancing the cardiovascular risk. Fewer Bacteroidetes and more Firmicutes seem to characterize the gut microbiota of obese people as compared with that of lean individuals. This difference translates into an increased efficiency of microbiota of obese individuals in harvesting energy from otherwise indigestible carbohydrates. Furthermore, the microbiota also seems able to favor fat accumulation. Indeed, studies performed in germ-free animals have demonstrated that conventionalization of sterile intestine with gut microbiota is associated with an enhanced expression of various lipogenic genes in different tissues, i.e., hepatic, adipose, and muscle tissues. Finally, the microbiota favors systemic exposure to the lipopolysaccharides (LPSs), large glycolipids derived from the outer membrane of Gram-negative bacteria. LPSs can cause a condition of “metabolic endotoxemia” characterized by low-grade inflammation, insulin resistance, and augmented cardiovascular risk. LPSs are a powerful trigger for the innate immune system response. Upon binding to the Toll-like receptor 4 and its coreceptors, LPSs trigger a cascade of responses ultimately resulting in the release of proinflammatory molecules that interfere with modulation of glucose and insulin metabolism, promote development and rupture of the atherosclerotic plaque, and favor progression of fatty liver disease to steatohepatitis. This review gives a comprehensive breakdown of the interaction among gut microbiota, LPSs, and the innate immune system in the development of obesity and promotion of an individual’s cardiovascular risk.

Obesity is a frequent cause of insulin resistance and poses a major risk for diabetes. Abnormal fat deposition within skeletal muscle has been identified as a mechanism of obesity-associated insulin resistance. We tested the hypothesis that dietary lipid deprivation may selectively deplete intramyocellular lipids, thereby reversing insulin resistance. Whole-body insulin sensitivity (by the insulin clamp technique), intramyocellular lipids (by quantitative histochemistry on quadriceps muscle biopsies), muscle insulin action (as the expression of Glut4 glucose transporters), and postprandial lipemia were measured in 20 morbidly obese patients (BMI = 49 ± 8 [mean ± SD] kg · m⁻²) and 7 nonobese control subjects. Patients were restudied 6 months later after biliopancreatic diversion (BPD; n = 8), an operation that induces predominant lipid malabsorption, or hypocaloric diet (n = 9). At 6 months, BPD had caused the loss of 33 ± 10 kg through lipid malabsorption (documented by a flat postprandial triglyceride profile). Despite an attained BMI still in the obese range (39 ± 8 kg · m⁻²), insulin resistance (23 ± 3 μmol/min per kg of fat-free mass; P < 0.001 vs. 53 ± 13 of control subjects) was fully reversed (52 ± 11 μmol/min per kg of fat-free mass; NS versus control subjects). In parallel with this change, intramyocellular—but not perivascular or interfibrillar—lipid accumulation decreased (1.63 ± 1.06 to 0.22 ± 0.44 score units; P < 0.01; NS vs. 0.07 ± 0.19 of control subjects), Glut4 expression was restored, and circulating leptin concentrations were normalized. In the diet group, a weight loss of 14 ± 12 kg was accompanied by very modest changes in insulin sensitivity and intramyocellular lipid contents. We conclude that lipid deprivation selectively depletes intramyocellular lipid stores and induces a normal metabolic state (in terms of insulin-mediated whole-body glucose disposal, intracellular insulin signaling, and circulating leptin levels) despite a persistent excess of total body fat mass.

The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant conditions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expression is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF)α or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean expression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correlation between muscle Mfn2 expression and insulin sensitivity was again detected. In vitro experiments revealed an inhibitory effect of TNFα or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNFα and interleukin-6 downregulate Mfn2 expression and may participate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a molecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes.

Currently, there are no data in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 ± 4.3 to 65.73 ± 3.22 μmol · kg fat-free mass⁻¹ · min⁻¹ at 1 week and to 64.73 ± 3.42 μmol · kg fat-free mass⁻¹ · min⁻¹ at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 ± 20.07 to 70.0.2 ± 8.14 and 83.24 ± 8.28 pmol/min per m²; P < 0.01) and total insulin output (43.76 ± 4.07 to 25.48 ± 1.69 and 30.50 ± 4.71 nmol/m²; P < 0.05) dramatically decreased, while a significant improvement in β-cell glucose sensitivity was observed. Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 ± 1.99 to 6.58 ± 1.72 pmol/l at 1 week and 5.83 ± 0.80 pmol/l at 4 weeks) significantly (P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 ± 0.16 to 3.42 ± 0.41 pmol/l at 1 week and 3.62 ± 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing β-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum.