Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.