Brown fat, a type of adipose tissue that is rich in mitochondria, is found in in

Question

Brown fat, a type of adipose tissue that is rich in mitochondria, is found in infants and plays a central role in thermoregulation. Mitochondria in brown fat express a protein known as Uncoupling Protein 1 (UCP-1) that (similar to the effects of DNP) uncouple oxidation of NADH and FADH2 from phosphorylation. More recently, brown fat was shown to be present in adults as well. There is considerable interest in trying to develop pharmacological approaches that would stimulate the conversion of white fat into brown fat. If drugs were developed that increased the conversion of white fat to brown fat, would this represent a potential mechanism to promote weight loss in obese individuals? Explain your answer.

Explanation / Answer

With time in culture, brown preadipocytes “spontaneously” differentiate morphologically into brown adipocytes, corresponding to “adipose conversion” in white adipocytes. The alteration in morphology is parallelled by and caused by increased expression of genes related to lipid metabolism and, noteworthy for brown adipocytes, of genes related to mitochondrial function. It is also parallelled by an altered expression of a series of transcription factors, as detailed in Figure 10. A “master controller” for this conversion could be perceived but has not been identified. Although differentiation is a successive process, an understanding is facilitated if the process is seen as a rather abrupt switch from the cells being brown preadipocytes to being mature brown adipocytes. This switch is parallelled by a switch in the type of response of the cells to norepinephrine: from stimulation of proliferation to stimulation of differentiation (and inhibition of apoptosis). All these adrenergic effects make physiological sense because they mean that recruitment is promoted under conditions of a constant demand for thermogenesis, but it is unknown how the switch in norepinephrine effect is achieved at the nuclear level. Norepinephrine thus promotes the differentiation process in general in brown adipose tissue, through cAMP-dependent processes. The pathways have not been well characterized. In some cases, a classical cAMP/protein kinase A/CREB phosphorylation pathway is probably utilized (see sect. IIA), leading directly to increased expression of certain enzymes, etc. In other cases, the effect may be indirect, with norepinephrine, perhaps also via CREB phosphorylation, enhancing the expression of transcription factors that in their turn promote differentiation. Thus norepinephrine increases C/EBP levels (649). From in vivo experiments, it is also likely that adrenergic stimulation increases PGC-1 gene expression (265, 633), which may largely be causative of the norepinephrineinduced increase in the degree of differentiation. Constant norepinephrine stimulation is thus the mechanism for generating the cellular components of the thermogenic state, including an increased amount of mitochondria (323, 551) well endowed with oxidative capacity for catabolism of fatty acids.

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