Joseph Proietto

Obesity rates are rising in all parts of the world. It is generally believed that this is because of the rapid change in food availability and the removal of the obligatory need to do physical work. This chapter will discuss the powerful evidence that while these changes in lifestyle facilitate the development of obesity, on their own they cannot be the causes of obesity. They provide the necessary circumstances for the multiple genes selected over millions of years to improve the survival of the species, by causing excess deposition of stored energy as fat. There are single gene mutations that lead to severe obesity, such as a mutation in the leptin gene or the melanocortin 4 receptor gene or combinations of gene polymorphisms that interact to give different degrees of overweight. There are also multiple mechanisms described where environmental situations epigenetically imprint genes to lead to obesity. We also have two negative feedback systems to prevent obesity in genetically lean individuals. Finally, the body defends weight vigorously by increasing hunger and reducing energy expenditure when someone loses weight. This would not occur if obesity was only due to lifestyle changes.

Purpose: Prader-Willi syndrome (PWS) is characterised by childhood-onset hyperphagia and obesity however limited data are available to guide treatment of obesity in this population. We aimed to evaluate the safety, tolerability, and efficacy of intensive medical weight loss interventions (very-low-energy diets [VLED] and/or pharmacotherapy) in individuals with PWS attending a specialist obesity management service. Methods: A retrospective audit was undertaken of individuals with PWS attending the Austin Health Weight Control Clinic between January 2010-April 2021. Main outcome measures were weight outcomes, duration of use, and adverse effects. Results: Data were available for 18 patients, of whom 15 were treated with intensive weight loss interventions. Median (interquartile range, IQR) age at baseline was 20 years (19–32) with median body weight 90 kg (75–118) and BMI 37 kg/m² (30–51). Median weight loss during VLED (n = 7) was 14 kg (1–20 kg) over 60 weeks. Median weight loss with phentermine-topiramate (n = 7) was 17 kg (IQR 9–19 kg) over 56 weeks. Median weight loss with liraglutide 0.6–3 mg (n = 7), prescribed with topiramate in 3 individuals, was 9 kg (2–14 kg) over 96 weeks. Naltrexone-bupropion resulted in weight loss in 2 of 4 individuals. Thirteen individuals achieved ≥10% weight loss but only 5 individuals maintained ≥10% weight loss at last follow-up. Five individuals discontinued pharmacotherapy due to adverse effects. Conclusions: VLED and pharmacotherapy can achieve substantial weight loss in some individuals with PWS though non-adherence results in substantial weight regain. Adverse effects were ascribed to phentermine and topiramate, whereas liraglutide was well-tolerated in this population.

Patients with obesity often require drug therapy to maintain the weight loss achieved by diet.

Objective The aim of this study was to determine whether the hormone changes following weight loss are proportional to the degree of weight loss and to starting BMI. Methods A very low-energy diet was used to achieve 15% weight loss. Fasting and postprandial gut hormones and leptin were measured during a meal test at baseline and at 5% (1%), 10% (2%), and 15% (2.5%) weight loss. Linear mixed-effects models were used to analyze hormone changes. Results From baseline to 5% weight loss, decreases were seen in fasting concentrations of leptin (-8.25 ng/mL; p < 0.001), amylin (-21.3 pg/mL; p < 0.001), and glucagon-like peptide 1 (-59.55 pg/mL; p < 0.001). There was a small further reduction in leptin between 5% and 15% weight loss (-1.88 ng/mL; p = 0.019) but not in glucagon-like peptide 1 and amylin. Fasting ghrelin showed a significant increase at 10% weight loss (41.64 pg/mL; p = 0.002), with a nonsignificant increase from 10% to 15% loss (26.03 pg/mL; p = 0.065). Postprandial changes in hormone levels were variable. There was no correlation between baseline weight and the degree of hormone changes. Conclusions The majority of changes in fasting gut hormones and leptin occurred in early weight loss, with minor further changes up to 15% weight loss. Starting weight did not affect the degree of hormone change.

Objective: This study examined the effectiveness of a nonsurgical, preconception weight loss intervention on pregnancy outcomes in women with obesity.Methods: This was a two‐arm, parallel‐group randomized controlled trial. A total of 164 women with BMI 30 to 55 kg/m² who were aged 18 to 38 years and planning pregnancy were randomized to a 12‐week standard dietary intervention (SDI; n = 79) or a modified very low‐energy diet (VLED; n = 85). Participants were observed for ≤48 weeks while trying for pregnancy and then during pregnancy. The primary outcome was maternal fasting plasma glucose at 26 to 28 weeks’ gestation. Exploratory outcomes were individual and composite obesity‐related adverse pregnancy outcomes.Results: Weight loss was greater in the VLED group (SDI 3.2 [0.6] kg vs. VLED 13.0 [0.5] kg, p < 0.01). In completers who had a singleton live birth (SDI 22/79 vs. VLED 35/85, p = 0.10), there was no difference in fasting glucose at 26 to 28 weeks’ gestation (SDI 4.8[0.2] mmol/L vs. VLED 4.6 [0.1] mmol/L, p = 0.42). However, the composite of adverse pregnancy outcomes was significantly lower in the VLED group (p < 0.001).Conclusions: Substantial prepregnancy weight loss in women with obesity does not alter fasting glucose at 26 to 28 weeks’ gestation but does reduce a composite of adverse pregnancy outcomes. A better understanding of metabolic changes in pregnancy after preconception weight loss may assist in improving maternal and neonatal health outcomes.

This study from Hunan in China reports that patients admitted to hospital with COVID-19 infection who were treated with insulin had 27.2% mortality compared with 3.5% mortality in patients with type 2 diabetes not treated by insulin. Further analysis showed that insulin treatment was associated with enhanced systemic inflammation and aggravating injuries of vital organs. It is not possible to say if organ damage or increased inflammation was the main factor for the increased mortality. Why was there more inflammation with insulin treatment? Insulin therapy in insulin resistant states activates the inflammatory cascade {1}. Insulin signals through the PI3 kinase and MAP kinase pathways. Activation of MAP kinase pathways increases cytokine production while there is some evidence that activation of PI3 kinase inhibits cytokine production. Thus, in insulin-sensitive individuals insulin does not change cytokine production as it activates both arms of the signalling system. Insulin resistance impairs the PI3 kinase pathway but not the MAP kinase pathway {2}. Thus, when insulin is given, the MAP kinase pathway is activated with no inhibition from the PI3 kinase pathway, leading to enhanced cytokine production. Insulin increases blood pressure and causes weight gain {3}. Insulin should be avoided in type 2 diabetes if at all possible. We now have many medications for type 2 diabetes that encourage weight loss, including metformin, GLP-1 analogues, SGLT2 inhibitors.

Obesity and osteoporosis are both common conditions with high rates of morbidity and mortality. There is a relationship between obesity and bone. There are multiple factors that influence the risk of fracture, including the quality of bone, the risk of falls, and the padding around the bone. These multiple factors partly explain the finding that obesity protects against fractures in some sites while increasing the risk in other parts of the body. While it is well known that increased weight builds bone, there are several mechanisms related to the obese state that make the bone more fragile. These include the increased production of bone marrow fat cells at the expense of bone-forming osteoblasts, an increase in inflammatory cytokines leading to the activation of bone-resorbing osteoclasts, mutations in theFTOgene, and obesity-induced increased osteoblast senescence. Surprisingly, the relationship between bone and obesity is not unidirectional; there is now evidence that osteocytes are able to regulate body weight by acting as weighing machines.

Summary: The prevalence of women of child‐bearing age with obesity continues to rise at an alarming rate. This has significant implications for both the short‐term and long‐term health of mother and offspring. Given the paucity of evidence‐based literature in this field, the preconception management of women with obesity is highly variable both between institutions and around the world. This systematic review aims to evaluate studies that inform us about the role of preconception weight loss in the fertility and pregnancy outcomes of women with obesity. Current therapeutic interventions are discussed, with a specific focus on the suitability of weight loss interventions for women with obesity planning pregnancy. There are significant knowledge gaps in the current literature; these are discussed and areas for future research are explored.