Obesity risk is associated with altered cerebral glucose metabolism and decreased μ-opioid and CB1 receptor availability

Background Obesity is a pressing public health concern worldwide. Novel pharmacological means are urgently needed to combat the increase of obesity and accompanying type 2 diabetes (T2D). Although fully established obesity is associated with neuromolecular alterations and insulin resistance in the brain, potential obesity-promoting mechanisms in the central nervous system have remained elusive. In this triple-tracer positron emission tomography study, we investigated whether brain insulin signaling, μ-opioid receptors (MORs) and cannabinoid CB1 receptors (CB1Rs) are associated with risk for developing obesity. Methods Subjects were 41 young non-obese males with variable obesity risk profiles. Obesity risk was assessed by subjects’ physical exercise habits, body mass index and familial risk factors, including parental obesity and T2D. Brain glucose uptake was quantified with [18F]FDG during hyperinsulinemic euglycemic clamp, MORs were quantified with [11C]carfentanil and CB1Rs with [18F]FMPEP-d2. Results Subjects with higher obesity risk had globally increased insulin-stimulated brain glucose uptake (19 high-risk subjects versus 19 low-risk subjects), and familial obesity risk factors were associated with increased brain glucose uptake (38 subjects) but decreased availability of MORs (41 subjects) and CB1Rs (36 subjects). Conclusions These results suggest that the hereditary mechanisms promoting obesity may be partly mediated via insulin, opioid and endocannabinoid messaging systems in the brain.

Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosine-binding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237. Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation.

Association between Dietary Patterns, Breakfast Skipping and Familial Obesity among a Sample of Egyptian Families

AIM: To examine the association between dietary patterns, behaviors and the prevalence of familial obesity.SUBJECTS AND METHODS: Eighty three families, shared as volunteers comprised of 83 mothers and 155 offspring. Anthropometric measurements were reported including height and weight. Body mass index (BMI), weight/height, and weight/height Z score were calculated. Pattern of food intake was obtained by means of dietary interview consisting of a 24 hour recall, and a food frequency questionnaire.RESULTS: Data revealed that obesity was high among mothers reached 91.6% while obesity in the offspring was 24.5%. According to prevalence of obesity, families were divided to 4 groups, 8.43% of families were of normal weight, and 20.48% were obese. Food frequency consumption rate and food analysis revealed unhealthy food intake, especially in obese families. All groups reported high rate intake of sweets, pastries and beverage. Calories, carbohydrate, cholesterol and sodium were higher than the RDA in all mother’s groups, and adolescent group (2) compared to low daily intake of micronutrients especially calcium and vitamin D in all groups. More than half of all mothers and offspring skipped breakfast.CONCLUSION: Results of this study suggest that familial obesity increases the risk of offspring being obese, dietary habits might be involved in the development of obesity.