Causes, consequences, and treatment of metabolically unhealthy fat distribution.

An increase in fat mass is considered to be an important risk factor for the worldwide increase in type 2 diabetes and cardiovascular disease. However, for a given fat mass, there is a large variability in the risk prediction of these cardiometabolic diseases. For example, some lean people unexpectedly have a risk of type 2 diabetes and cardiovascular disease that is similar to the increased risk that is observed in most people who have obesity. What both of these phenotypes have in common is a very characteristic fat distribution. As a result, much focus has been given on the strong predictive power of increased visceral fat mass. However, an analysis of the causes of type 2 diabetes and cardiovascular disease, as well as comparisons to rare diseases such as lipodystrophy and studying genetically determined fat distribution in the general population, suggest that an impaired ability to expand subcutaneous fat in the lower part of the body is also important for predicting the incidence of these cardiometabolic diseases. This Review, first, addresses the identification of distinct fat distribution phenotypes and their risk of cardiometabolic diseases by discussing findings from published studies that have applied precise quantification of different fat depots. Second, this Review provides support for the theory that a lower amount of lower-body fat mass is equally important to a high amount of visceral fat mass as a determinant of cardiometabolic diseases. Third, this Review discusses the genetic and lifestyle-related causes of metabolically healthy and unhealthy fat distribution. Finally, this Review summarises and appraises the effectiveness of lifestyle-related interventions and pharmacological interventions for reducing visceral adiposity and maintaining lower-body fat mass to prevent and treat cardiometabolic diseases.