Anna Maria Siegert

Bio: Anna Maria Siegert is an academic researcher from University of Cambridge. The author has contributed to research in topics: Leptin receptor & Setmelanotide. The author has an hindex of 1, co-authored 1 publications receiving 10 citations.

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.

Abstract: Background Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in the control of mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variation influencing the population distribution of body-weight. At the end of 2020, the Food & Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency. Scope of review Here, we will chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target. Conclusions Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind the melanocortin receptors has brought a new drug to the market for obesity. This process provides a template of drug discovery for complex disorders, which in the case of setmelanotide took 25 years to go from a single gene to an approved drug.

The genetics of obesity: from discovery to biology

Abstract: The prevalence of obesity has tripled over the past four decades, imposing an enormous burden on people’s health. Polygenic (or common) obesity and rare, severe, early-onset monogenic obesity are often polarized as distinct diseases. However, gene discovery studies for both forms of obesity show that they have shared genetic and biological underpinnings, pointing to a key role for the brain in the control of body weight. Genome-wide association studies (GWAS) with increasing sample sizes and advances in sequencing technology are the main drivers behind a recent flurry of new discoveries. However, it is the post-GWAS, cross-disciplinary collaborations, which combine new omics technologies and analytical approaches, that have started to facilitate translation of genetic loci into meaningful biology and new avenues for treatment. In this Review, Loos and Yeo summarize our current understanding of the genetic underpinnings of monogenic and polygenic obesity. They highlight the commonalities revealed by recent studies and discuss the implications for treatment and prediction of obesity risk.

Obesity: Epidemiology, Pathophysiology, and Therapeutics.

Abstract: Obesity is a complex multifactorial disease that accumulated excess body fat leads to negative effects on health. Obesity continues to accelerate resulting in an unprecedented epidemic that shows no significant signs of slowing down any time soon. Raised body mass index (BMI) is a risk factor for noncommunicable diseases such as diabetes, cardiovascular diseases, and musculoskeletal disorders, resulting in dramatic decrease of life quality and expectancy. The main cause of obesity is long-term energy imbalance between consumed calories and expended calories. Here, we explore the biological mechanisms of obesity with the aim of providing actionable treatment strategies to achieve a healthy body weight from nature to nurture. This review summarizes the global trends in obesity with a special focus on the pathogenesis of obesity from genetic factors to epigenetic factors, from social environmental factors to microenvironment factors. Against this background, we discuss several possible intervention strategies to minimize BMI.

A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on

Abstract: The WHO just released in May 2022 a report on the state of the obesity pandemic in Europe, stating that 60% of citizens in the area of Europe are either overweight or obese, and highlighting the implications of the obesity pandemic, especially as it interacts with the COVID pandemic to create a twin pandemic, to increase morbidity and mortality. Obesity is a complex disease which has reached pandemic dimensions. The worldwide prevalence of obesity has nearly tripled since 1975, mainly due to the adoption of a progressively more sedentary lifestyle and the consumption of less healthy diets. We first report herein updated prevalence rates of overweight and obesity by sex, age, and region first in Europe, per the WHO report, and then worldwide between 1980 and 2019, as we analyze and present herein the data provided by the Global Burden of Disease Study. The prevalence of obesity is higher in women than in men of any age and the prevalence of both overweight and obesity increases with age and has reached their highest point between the ages of 50 to 65 years showing a slight downward trend afterwards. The age-standardized prevalence of obesity has increased from 4.6% in 1980 to 14.0% in 2019. The American and European region have the highest obesity prevalence and the USA and Russia are the countries with the most obese residents. Given dire implications in terms of comorbidities and mortality, these updated epidemiological findings call for coordinated actions from local and regional governments, the scientific community and individual patients alike, as well as the food industry for the obesity pandemic to be controlled and alleviated. We can hopefully learn from the COVID-19 pandemic, where collaborative efforts worldwide, focused intense work at both the local and global level and well-coordinated leadership have demonstrated that humankind is capable of amazing accomplishments by leveraging science and public health, and that we can finally make strides in terms of understanding and combating the obesity pandemic and its dire comorbidities including diabetes, NAFLD, CVD and obesity associated malignancies.

Signaling pathways in obesity: mechanisms and therapeutic interventions

Abstract: Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.

The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits

Abstract: Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.