Table 2.

Adipocyte-selective gene deletions of components involved in insulin stimulation of glucose utilization and inhibition of lipolysis result in parallel effects on whole body insulin sensitivity or glucose tolerance (GTT). Experimental manipulation of the listed insulin signaling elements or targets specifically in all adipocyte types causes similar effects on systemic glucose tolerance. Thus, gene knockout of elements selectively in adipocytes that drive the pathway of insulin stimulation of glucose uptake and esterification to triglyceride (for example, insulin receptor, Akt) also attenuate whole body insulin sensitivity and enhance obesity-induced insulin resistance. Conversely, adipose-selective deletions of genes that enhance insulin signaling in adipocytes (for example, p85 insufficiency that stimulates PI 3K or PIP3 phosphatase PTEN) cause increased systemic insulin sensitivity and attenuate insulin resistance in obesity. In concert with these results, adipose-selective deletion of genes encoding downstream targets of insulin signaling such as glucose transporter GLUT4 or fatty acid esterification enzyme DGAT1 diminish whole body glucose tolerance and enhance insulin resistance. Adipose-selective gene deletion of ATGL mimics the action of insulin to decrease adipocyte lipolysis, which enhances systemic insulin sensitivity by decreasing hepatic steatosis and insulin resistance. In contrast, when insulin signaling elements are deleted specifically in BAT, mixed results are observed on systemic glucose tolerance.

Insulin signaling pathway component	Experimental perturbation	Adipocyte insulin action	Systemic insulin sensitivity or GTT	Ref.
Insulin Receptor	Adipose-selective KO	Decreased	Decreased	[110]
	BAT-selective KO	Decreased	Insulin secretion defect	[111]
p85/PI 3 K	Adipose-selective Insufficiency	Increased	Increased	[115]
PIP3	Adipose-selective PTEN KO	Increased	Increased	[116]
Akt 1/2	Adipose-selective KO	Decreased	Decreased	[112]
AS160	Human mutation	Decreased	Decreased	[123]
Raptor/mTORC1.	Adipose-selective KO	Decreased	Decreased	[113]
Rictor/mTORC2.	BAT/Beige-selective KO.	Decreased	Increased	[195]
GLUT4	Adipose-selective KO	Decreased	Decreased	[114]
	Adipose-selective Tg	Increased	Increased	[114]
DGAT1 (FA esterification)	Adipose-selective KO	Decreased	Decreased	[84,85]
ATGL (lipolysis lipase).	Adipose-selective KO	Mimics Insulin	Increased	[11,117]
	BAT/Beige-selective KO	Mimics Insulin	Glucose intolerance	[193]