The ‘Novel’‘Uncoupling’ Proteins UCP2 and UCP3: What Do They Really do? Pros and Cons for Suggested Functions

Abstract

The scientifically novel, but evolutionarily ancient, so‐called uncoupling proteins 2 and 3 (UCP2, UCP3) are structually similar to the archetypical uncoupling protein UCP1. A series of suggestions have been forwarded for their physiological function. We discuss systematically here the pros and cons for these suggestions. We conclude that the novel UCPs do not seem to be physiologically relevant uncoupling proteins; the uncoupling property was apparently a late introduction into the subfamily through the evolution of UCP1. Physiological functions ascribed to UCP2 and UCP3 based on their purported uncoupling property may have to be revised (i.e. any type of thermogenesis, including protection against obesity, protection against the formation of reactive oxygen species and thermogenic involvement in the fever response). The presence of a mixed genetic background in most published studies of UCP2 or UCP3 gene‐ablated mice also means that data concerning marked differences in diabetes propensity, infection sensitivity and production of reactive oxygen species may require confirmation in backcrossed mice. The increased expression of UCP2 and UCP3 under conditions of increased fatty acid metabolism implies an as yet undefined role in lipid metabolism. Thus, the novel UCPs should probably be considered as mitochondrial carriers, and the challenge now is to identify the transported molecule.

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

“…It is therefore premature to draw a definitive conclusion on its modulation and it is thus possible to tentatively conclude that in our study an interaction occurred between two different stimuli on UCP1 expression: HFD having a negative or neutral effect and TLQP-21 determining a stimulatory effect. On the contrary, without any effect of TLQP-21, the mitochondrial UCP2 was clearly upregulated by the high fat feeding [1] in agreement with its putative role in the control of ATP synthesis, regulation of fatty acid metabolism and control of reactive oxygen species production in metabolically active tissues [12,51].…”

Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance

“…These topics have been extensively reviewed during the past few years [40][41][42][43][44][45][46][47][48][49], but within the context of this review focusing on adaptive thermogenesis and fat metabolism, it is important to point out that it is debatable whether these UCP1-homologues have genuine uncoupling properties for the following reasons:…”

Asociación de variantes en genes de las proteínas desacoplantes con diabetes mellitus tipo 2 en una población del nordeste colombiano

“…Los genes de las proteínas desacoplantes se han asociado con varias características fenotípicas implicadas en la diabetes mellitus tipo 2, como son la secreción de la insulina, la protección contra especies reactivas de oxígeno, la alteración en el metabolismo de los lípidos y la obesidad (5)(6)(7). Existe una gran homología entre sus secuencias: UCP2 y UCP3 tienen identidad con UCP1 de 55% y 57%, respectivamente; y UCP2 y UCP3 son 57% idénticas entre sí; el gen UCP1 está ubicado en la región 4q28-q31 y, UCP2 y UCP3, en la 11q13, con una distancia de 7 kb entre ellos (8).…”

“…Estas relaciones varían según la proteína particular y su expresión en diferentes tejidos. En diversos estudios se han hallado, principalmente, relaciones entre alteraciones en UCP1 y UCP3, con obesidad y metabolismo de lípidos, en UCP2, con fallas en la secreción de insulina, y en UCP2 y UCP3, con protección contra especies reactivas de oxígeno (6,7,10,11). Además, en el último año, UCP1 y UCP3 se han asociado con la secreción de insulina estimulada por glucosa (5,9).…”