We replicated a recognized model of mouse lipodystrophy [18] as a basis for our efficacy studies, primarily because it is a fully penetrant model of adipose deficiency, and has been used previously to assess the tissue-specific effect of anti-diabetic therapeutics [21]. Our initial observations of little-to-no effects of FGF21 in these mice were striking. A confounding aspect of the Tg mice is that, in addition to their reduction in WAT without changes in body weight, they replicate human lipodystrophy and exhibit multi-phenotypic consequences of adipose loss, namely, hepatomegaly/steatosis, insulin resistance, glucose intolerance, and chronic inflammation [22], and present hypotriglyceridemia which we attribute to the FVB genetic background Thus the lack of efficacy does not indicate directly that WAT is the pharmacological site of action of FGF21 since other tissues could also be resistant to FGF21 as a secondary consequence of reduced adipose mass; however, it does highlight the importance of adipose tissue per se. Another possibility is that these Tg mice have normal body weight and very little adipose tissue so they cannot become much leaner with FGF21 treatment. An
