Paper of the Month
NOVEMBER 2018 – An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance
In November Knut Mai, coordinator Clinical Research Unit (CRU), and his team received the Paper of the Month award.
Mai K, Li L, Wiegand S, Brachs M, Leupelt V, Ernert A, Kühnen P, Hübner N, Robinson P, Chen W, Krude H, Spranger J. An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance. Diabetes. 2019 Jan;68(1):57-65. doi: 10.2337/db18-0440. Epub 2018 Nov 2.
Lifestyle-based weight loss interventions frequently demonstrate long-term inefficiency and weight regain. Identification of underlying mechanisms and predictors to identify subjects who will benefit from lifestyle-based weight loss strategies is urgently required. We analyzed 143 adults of the randomized Maintain trial (Maintain-Adults) after intended weight loss to identify mechanisms contributing to the regulation of body weight maintenance. Unbiased RNA sequencing of adipose and skeletal muscle biopsies revealed fatty acid metabolism as a key pathway modified by weight loss. Variability of key enzymes of this pathway, estimates of substrate oxidation, and specific serum acylcarnitine (AC) species, representing a systemic snapshot of in vivo substrate flux, predicted body weight maintenance (defined as continuous or dichotomized [< or ≥3% weight regain] variable) 18 months after intended weight loss in the entire cohort. Key results were confirmed in a similar randomized controlled trial in 137 children and adolescents (Maintain-Children), which investigated the same paradigm in a pediatric cohort. These data suggest that adaption of lipid utilization in response to negative energy balance contributes to subsequent weight maintenance. Particularly a functional role for circulating ACs, which have been suggested to reflect intracellular substrate utilization, as mediators between peripheral energy stores and control of long-term energy homeostasis was indicated.
In November, Knut Mai, coordinator of the BIH Clinical Research Unit (CRU), and his team received the Paper of the Month. We talked to him about the excellent publication:
What do you research and what is your main focus? What motivates you in your work?
My research group focuses on analyzing the interaction of endocrine, metabolic, and nutritive factors in the pathogenesis of diseases, with a particular emphasis on more precisely characterizing the interaction of metabolic processes and endocrine control systems involved in body weight regulation, insulin resistance, and lipid utilization (which are aspects of fat metabolism). These investigations aim to gain a better understanding of obesity and type 2 diabetes mellitus. My group’s research projects are primarily clinical/translational in nature and examine the various metabolic tissue compartments with regard to their metabolic and hormonal significance. The interaction with and integration of various collaboration partners, which is necessary in order to add value to the research, is a big motivator for my work.
What is the core message of your paper, and how does your study differ from the work of other scientists in this field?
A central problem in the treatment of obesity is that in a majority of cases patients experience weight regain after initially successful weight loss. In the present study, which was carried out under a clinical research collaboration, we investigated to what extent a longer-term weight maintenance intervention can be used to stabilize weight loss among adults and children/youth, while also examining the processes involved in the regaining of lost weight. Using RNA sequencing, we succeeded in characterizing various elements of adipocyte lipid utilization as key weight maintenance parameters. Analogously, we identified specific acylcarnitine species – expressed through increased lipid utilization at the systemic level – as predictors of weight regain.
Who did you collaborate with on this paper? Who were the key participants?
The results published in this paper were only made possible by the extensive collaboration within and outside the clinical research group. First and foremost, I must mention the collaboration with Susanna Wiegand, Peter Kühnen, Andrea Ernert, and Heiko Krude from the pediatric endocrinology. We were able to successfully conduct the two big intervention studies through collaboration with the study teams from Charité’s Departments of Pediatric Endocrinology and Diabetology and of Endocrinology, Diabetes and Nutrition. Through collaboration with Norbert Hübner and Wei Chen of the MDC and Peter Robinson of Charité’s Institute of Medical Genetics and Human Genetics, Maria Brach from my research group succeeded in identifying the gene responsible for lipid utilization. The biochemical analyses were done in our own clinic at the Center for Cardiovascular Research (CCR) and led by Maria Brachs.
What are the next steps for the project and what are the possible implications of your findings for patients?
The results published in this paper are only the beginning of our studies. We next want to collaborate closely with the animal experimental unit of our clinic at the CCR to identify further molecular mechanisms that play a crucial role in body weight regulation, energy balance, and insulin sensitivity and evaluate these for their suitability as potential therapeutic targets. A particular focus of our continuing studies will be the regulation of local and systemic lipid utilization.