Mitochondria perform essential roles as crucial organelles for cellular and systemic energy homeostasis, and as signaling hubs, which coordinate nuclear transcriptional responses to the intra- and extra-cellular environment. Complex human diseases, including diabetes, obesity, fatty liver disease and aging-related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OxPhos) function. However, a recent series of studies in animal models have revealed that an integrated response to tolerable mitochondrial stress appears to render cells less susceptible to subsequent aging processes and metabolic stresses, which is a key feature of mitohormesis. The mitochondrial unfolded protein response (UPRmt) is a central part of the mitohormetic response and is a retrograde signaling pathway, which utilizes the mitochondria-to-nucleus communication network. Our understanding of the UPRmt has contributed to elucidating the role of mitochondria in metabolic adaptation and lifespan regulation. In this review, we discuss and integrate recent data from the literature on the present status of mitochondrial OxPhos function in the development of metabolic diseases, relying on evidence from human and other animal studies, which points to alterations in mitochondrial function as a key factor in the regulation of metabolic diseases and conclude with a discussion on the specific roles of UPRmt and mitohormesis as a novel therapeutic strategy for the treatment of obesity and insulin resistance.