Nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with roles in cellular metabolism and energy homeostasis, was investigated as a novel anti-obesity drug target with promising results, according to research published this week in Biochemical Pharmacology.
"As fat cells grow larger, they begin to overexpress a protein that acts as a metabolic brake that slows down fat cell metabolism, making it harder for these cells to burn accumulating fat," said senior author Stanley Watowich, University of Texas Medical Branch (UTMB) associate professor in the department of biochemistry and molecular biology. "In addition, as the fat tissue expands, they secrete greater amounts of hormones and pro-inflammatory signals that are responsible for several chronic diseases, including type 2 diabetes and cardiovascular disease."
The researchers developed a series of small molecule NNMT inhibitors that block this metabolic brake from operating in obese white fat cells. By blocking this metabolic brake, they were able to increase the metabolism within white fat cells.
In the study, mice were fed a high-fat diet until they became obese and then received either the drug or a placebo. Following 10 days of drug treatment, researchers found that the obese mice receiving the actual drug lost more than 7% of their total body weight and their white fat tissue mass and cell size decreased by 30% compared with the placebo group. In addition, blood cholesterol in drug-treated mice was lowered to normal levels, similar to those of non-obese mice.
Placebo-treated mice continued to accumulate white fat and gain weight throughout the study. Interestingly, mice in both the drug-treated and placebo groups consumed the same amount of food during the course of the study period, showing that the fat loss was not due to appetite suppression.
"Blocking the action of the fat cell brake provides an innovative 'fat'-specific mechanism to increase cell metabolism and reduce the size of white fat deposits, thereby treating a root cause of obesity and related metabolic diseases," said senior author Harshini Neelakantan, a UTMB research scientist in the department of biochemistry and molecular biology. "These initial results are encouraging and support further development of this technology as a new and more effective approach to combating metabolic diseases."