Inverted obesity Flashcards
(18 cards)
RNA sequencing of multiple organs (liver, adipose, intestine) at 9 days and 9 weeks post-RYGB in mice showed distinct temporal transcriptional patterns: early increases in β-oxidation and triglyceride breakdown genes, later increases in amino acid catabolism and circadian gene shifts; at 9 weeks, increased expression of beige fat markers like UCP1 and histological confirmation of beige-like adipocytes in subcutaneous WAT.
Reanalyiss of human RNA-seq and bioposy datra showed correlated gene expression patterns in liver, WAT and intestine as seen in mice.
Compared to weight -matched sham-operated controls, RYGB mcie showed greater transcriptional change across organs, increased energy expenditure and redcued expressioin of of orexigenic genes.
Zvi et al. (2018)
Metabolic effect of RYGB
Measured insulin clearance and hepatic insulin resistance in patients before and one week after RYGB, finding a 50% reduction in hepatic insulin resistance and sustained elevation of insulin clearance up to one year postoperatively, indicating rapid improvement in metabolic function.
Limitations: insulin clearance and insulin sensitivity can become uncoupled as some people with insulin resistance do not show reduced clearance.
Bojsen-Moller et al. (2013)
Anti-diabetic effect of RYGB
In observational study of RYGB patients, postprandial GLP-1 and PYY profiles increased as early as two days after surgery.
Le Roux et al. (2007)
Timeframe of RYGB response
In observational cohorts split by excess weight loss after RYGB, mean postprandial GLP-1 response was ~50% higher in good versus poor responders, with proportional decreases in appetite. Greater ghrelin suppression was associated with better weight loss outcomes.
Dirksen et al. (2013)
Effects of RYGB stratified by response
Randomized test in 9 T2D patients post-RYGB comparing saline versus Ex-9 (GLP-1R antagonist) infusions after a liquid meal: post-RYGB, GLP-1 rose 8-fold, β-cell glucose sensitivity and insulin secretion rate increased significantly, and Ex-9 reversed these improvements and worsened glucose tolerance (measured by postprandial glucose levels), confirming GLP-1’s role in enhanced β-cell function.
Small smaple size (n=9); no direct measurements of hepatic glucose production so hard to fully isolate the effect of GLP-1 on systemic glucose metabolism vs insulin secretion alone; β cell function clearly imparied by Ex-9 but glucose tolerance only moderately worsened so potential rise in non-insulin dependent glucose disposal which was not measured,
Jorgensen et al. (2013)
Effects of GLP-1
Single dose of a long-acting oxyntomodulin (OXM) analogue administered to rodents led to a 10% increase in oxygen consumption over 12 hours independent of locomotor activity; effect was mediated by glucagon receptor activation since a mutant OX-2R-Glu3 peptide without glucagon activity did not increase thermogenesis.
Pair-fed rats - the OX-SR treated rats lost weight, the WT gained weight
Male rodents ony; OXM long-acting analogue wasn’t native OXM; metabolic effect was only measured over 24 hours; no direct measurements of thermogenesis e.g. thermal imaging of BAT; side effects of glucagon activation e.g. gluconeogenesis not measured.
Scott et al. (2018)
Effects of oxyntomodulin
Functional MRI in RYGB patients one month after surgery showed reduced mesolimbic reward pathway activation in response to high-palatable (but not low-palatable) food cues compared to pre-surgery, suggesting altered central reward signaling underlies changes in feeding behavior.
Ochner et al. (2011)
Effects of RYGB on the brain
Developed a DREADD mouse model to selectively activate Gq-coupled signaling in enteroendocrine cells using CNO: activation of enterochromaffin cells induced conditioned taste aversion via serotonin and substance P, while activation of CCK and GLP-1 producing cells induced conditioned flavor preference, demonstrating gut EEC activation modulates food-seeking behavior.
Bai et al. (2022)
Effect of RYGB on taste
Randomized 195 adults post-8-week low-calorie diet to exercise+placebo, liraglutide, exercise+liraglutide, or placebo: after one year, exercise lost 4.1kg, liraglutide 6.8kg, combo 9.5kg; combo improved HbA1c, insulin sensitivity, fitness, and emotional well-being, showing additive effects of pharmacotherapy and exercise.
Lundgren et al. (2021)
Efficacy of prescribed exercise
In mice, intracerebroventricular administration of liraglutide into the ventromedial hypothalamus increased energy expenditure and body weight loss and raised UCP1 levels in both BAT and WAT, compared to mice that were pair-fed and given a vehicle placebo.
Berioá et al. (2014)
Effect of GLP-1 on thermogenesis
26-week double-blind, placebo-controlled trial in 50 T2D patients comparing liraglutide versus placebo: liraglutide reduced resting energy expenditure (measured by indirect calorimetry after 4, 12, and 26 weeks and does not affect the fat fraction in supraclavicular BAT measured by MRI, indicating central effects may differ between rodents and humans.
Van Eyk et al. (2020)
Effect of GLP-1 on thermogenesis
Female mice fed a Western diet for 4 weeks were infused intracerebroventricularly with MC3/4R antagonist SHU9119 or vehicle for two weeks: antagonist-treated mice exhibited decreased BAT activity (via triglyceride uptake, energy expenditure, fat oxidation), suggesting central melanocortin signaling is required for BAT activation.
Limitations: no direct measurements of BAT activity in the sense of quantifying contribution to thermogenesis or measuring oxygen consumption; only female mice; delivery of SHU91219 intracerebroventricularly may not accurately reflect the phsyiological or clinical relevance of systemic melanocortin system modulation.
Kooijman et al. (2014)
Thermogenetic effect of melanocortin
Double BMP8B knockout female mice exhibited impaired thermogenesis, reduced metabolic rate, and weight gain despite hypophagia; BAT morphology was normal but lipid droplets were larger after high-fat diet, implicating BMP8B in sympathetic-stimulated thermogenic function.
Whittle et al. (2012)
Thermogenetic effects of BMPs
Injection of BMP8B into male rats did not increase body or BAT temperature, suggesting gender dimorphism or species differences limit BMP8B’s therapeutic potential for thermogenesis.
Martins et al. (2016)
Thermogenetic effects of BMPs
Tpcn1/2 double knockout mice developed mature-onset obesity with lower interscapular BAT temperature and lean-mass–adjusted oxygen consumption despite equal food intake; they had lower serum NEFA and decreased HSL expression, indicating defects in adrenergic signaling and BAT lipid availability.
Expression of β adrenergic mRNA was lower int he KO suggesting a defect in adrenergic signalling
Lear et al. (2014)
Thermogenetic effect of intracellular calcium signalling
Analyzed sperm DNA methylation in obese men and post-RYGB patients: obese men’s sperm showed altered methylation and small RNA expression patterns; one week post-RYGB changes began and became extensive by one year, highlighting rapid epigenetic remodeling in gametes.
Methylation changes were not observed in blood or adipose tissue.
Donkin et al. (2016)
Epigenetic effect of obesity
In C. elegans, F0 worms trained to associate isomyl alcohol (IAA) with starvation produced F1 offspring that avoided IAA without prior exposure; inherited response lasted only in F1, accompanied by nuclear translocation of DAF-16/FOXO in F1 and F2.
Crosses showed that only paternal transmissino i.e. via sperm could pass on the acquired cellular changes.
Deshe et al. (2023)
Inheritance of physiological stress
Delivering a structured, intensive weight-management programme in routine primary care was effective in promoting and maintaining weight loss
Flexible total diet replacement with optional extensions to adapt to progress made
Remission was most likely in those diagnosed more recently i.e. there is a window of opportunity for remission
Remission is strongly linked to degree of weight loss
Deprescribing as a personalised outcome
Lean et al (2018)
Personalised treatment plans
