Metabolic syndrome (MetS) is a conglomeration of several risk factors for cardiovascular disease, with obesity currently being one of the common causes of disability and death in the United States.1 Underlying the obesity, however, there is metabolic imbalance that could be exacerbating the issue of metabolic syndrome.2 Approximately 34% of adults over 20 years old matched the criteria for metabolic syndrome.3 The risk factors for cardiovascular disease (CVD) associated with metabolic syndrome can, over time, lead to severe CVDs, such as heart failure (HF).4 Metabolic syndrome can also lead to developing metabolic heart disease over time. Understanding the development of cardiac hypertrophy and fibrosis in diet-induced metabolic heart disease allow development of an early treatment of metabolic heart disease (MHD) and HF. This study looked at one potential mediator and its role in cardiac hypertrophy and fibrosis, follistatin-like 3 (FSTL3). FSTL3 is an extracellular antagonist of members of the TGF-β superfamily. The goal of our study was to determine the effect, if any, a knockout of FSTL3 would have on the development of cardiac hypertrophy and fibrosis after a high-fat, high-sucrose diet for five months. FSTL3 knockout mice were given a high-fat, high-sucrose (HFHS) diet for five months. These mice were then sacrificed and their hearts were analyzed for cardiac myocyte hypertrophy and interstitial fibrosis using histological methods. After five months on the HFHS diet, wild-type (WT) mice had cardiac hypertrophy. In FLRG KO mice the diet-induced cardiac hypertrophy was attenuated. WT HFHS-fed mice developed interstitial fibrosis, and FLRG KO HFHS developed more accentuated interstitial fibrosis than WT HFHS diet fed mice. This study is useful in suggesting that FTSL3 contributes to the pathogenesis of cardiac hypertrophy in MHD. FTSL3 may be a useful biomarker for cardiac hypertrophy in patients with suspected MHD, and may be a viable target for therapeutic interventions aimed at decreasing pathologic myocardial hypertrophy.