The role of mitochondrial dynamics in diet-influenced regulation of food intake and adiposity

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We have identified a role for mitochondrial dynamics (fission and fusion) in central regulation of feeding, energy- and glucose metabolism. We showed that mitochondrial fission is important for proper promotion of feeding and body weight gain by hypothalamic AgRP neurons, while mitochondrial fusion is critical for hypothalamic POMC neurons to support satiety and related adjustment of systemic glucose metabolism. In our preliminary studies we also found that interference with mitochondrial dynamics selectively in adult adipocytes has a robust impact on systemic metabolism, in which knockdown of the mitochondrial fusion protein, mitofusin 2 (Mfn2), resulted in rapid weight gain and elevated feeding of mice with concomitant elevations in hypothalamic transcripts for AgRP. These observations indicate weight gain is supported both centrally and peripherally by mitochondrial fission, and, that mitochondrial dynamics in either of the hypothalamus or adipocytes reciprocally impacts mitochondrial function in these tissues to affect behavior and systemic energy and glucose metabolism. In support of this, we revealed in an in vitro system that elevated fatty acid levels, which are critical for weight gain do promote mitochondrial fission. We observed that different fatty acids species have different effects on mitochondrial dynamics, and that altering dietary fat composition alone results in elevated in food intake and body weight gain. Taken together our observations gave impetus to the central hypothesis of this grant proposal that mitochondrial fission is a key dietary-influenced mechanism both in the hypothalamus and adipocytes that regulates body weight and adiposity. We propose the following Specific Aims to test our hypothesis: Specific aim 1 will assess the role of mitochondrial dynamics in food intake and energy expenditure by assessing the effects of both altered mitochondrial fission and fusion in mature adipocytes and in central feeding circuitry neurons. In addition, aim 1 will explore the afferent signaling from adipocytes that impacts the function of feeding circuitry neurons. Specific Aim 2 will use both in vitro and in vivo approaches to establish the role of hypothalamic and adipocyte mitochondrial dynamics on dietary fat-influenced food intake.