Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation

Notably, insulin-stimulated glucose uptake was mostly restricted to brown fat and we observed that RalA is dispensable for glucose uptake into eWAT in both gain-of-function and loss-of-function models. To examine further whether the impact of RalA on glucose uptake in adipocytes occurs in a cell-autonomous manner, we generated primary white adipocytes by differentiation of iWAT stromal vascular cells from control and KO mice. Moreover, insulin-stimulated glucose uptake in KO cells was significantly reduced in KO cells without disturbing upstream insulin signaling (Extended Data Fig. 1o,p). Many questions remain concerning the role of the RalA–Drp1 axis in the control of mitochondrial function in subcutaneous adipocytes. What is the mechanism by which RalA mRNA and protein expression are increased and RalGAP is decreased in adipose tissue during obesity?

If this happens, the router will send a message back to the host informing it that the packet was too big to pass forward. Firstly, maximum segment size (MSS) and Internet Control Message Protocol (ICMP) messages are exchanged between network endpoints. This allows for the negotiation of the maximum frame size that can be transmitted without the need for fragmentation. Although IP fragmentation can be problematic due to the overheads it creates and the potential for dropped or out-of-order fragments, it is often needed to allow packets to be transmitted across networks with different MTUs. IP fragmentation causes significant overheads that routers are not usually designed to cope with. During IP fragmentation, the router (or network switch) must create fragments and then re-assemble those fragments.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. ArXiv is committed to these values and only works with partners that adhere to them. As a result, a VPN can help by absorbing any IP fragmentation attacks meant for your local network.

Taken together, these data reveal that persistent elevation of RalA in obesity produces mitochondrial dysfunction in white adipocytes, with profound effects on systemic metabolism. Fully differentiated primary adipocytes in a 24-well plate were serum-starved in lipolysis medium (2% BSA-phenol-red-free DMEM) for 3 h. For insulin treatment, 100 nM insulin was added to cells for 30 min starting at 2.5 h of starvation. After starvation, the medium was replaced with 0.5 ml fresh lipolysis medium with vehicle, 1 μM CL, 100 nM insulin or in combination.

  1. In this fragmentation, the process is allocated a memory block of size more than the size of that process.
  2. The quantity of available memory is substantially reduced if there is too much external fragmentation.
  3. Fragmentation is a very common type of vegetative reproduction in plants.

The observation that adipocyte RalA controls overall systemic metabolism via this mechanism was noteworthy. We, and others, previously reported that RalA plays a key role in controlling the trafficking of GLUT4 vesicles in adipocytes https://traderoom.info/ and muscle22,23. Indeed, adipocytes treated with an RalA inhibitor26 or isolated from RalA KO mice showed dramatically reduced GLUT4 translocation to the plasma membrane, with less glucose uptake in response to insulin.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation.

What is an example of fragmentation in literature?

The new data blocks are necessarily scattered, slowing access due to seek time and rotational latency of the read/write head, and incurring additional overhead to manage additional locations. To establish whether this effect is cell-autonomous, we examined Drp1 phosphorylation in both immortalized and primary adipocytes. Consistent with in vivo results, Rala KO adipocytes showed a significantly higher Drp1 S637 after forskolin and β-adrenergic stimulation compared to WT cells (Fig. 5b,c and Extended Data Fig. fxtm cent account 6f–i). We also explored the effect of RalA on Drp1 S637 phosphorylation state using a specific Ral inhibitor that prevents activation and retains GTPase in the GDP-bound, inactive state26,46. Pretreatment with the pan-Ral inhibitor RBC8 significantly increased forskolin-stimulated Drp1 S637 phosphorylation in 3T3-L1 adipocytes (Extended Data Fig. 6j,k). Inhibition of RalA activity with RBC8 also increased forskolin-stimulated Drp1 S637 phosphorylation in the human primary adipocyte cell line SGBS (Fig. 5d,e).

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As a result, if you remove this condition, external fragmentation may be decreased. User processes are loaded and unloaded from the main memory, and processes are kept in memory blocks in the main memory. Many spaces remain after process loading and swapping that another process cannot load due to their size. Main memory is available, but its space is insufficient to load another process because of the dynamical allocation of main memory processes. Contiguous memory allocation allocates space to processes whenever the processes enter RAM. These RAM spaces are divided either by fixed partitioning or by dynamic partitioning.

Extended Data Fig. 6 Rala deletion in adipocytes did not affect cAMP production and HSL phosphorylation.

A fragmented system might potentially make better use of a storage device by utilizing every available storage block. For metabolic cage studies, mice were individually housed in Promethion metabolic cages maintained at 22 °C under a 12-h light–dark cycle. Before the experiment, mice were adapted to the metabolic cages for 2 d. The monitoring system records and calculates food intake, locomotor activity, oxygen consumption, CO2 production, RER and EE. Mice were provided with free access to water and food during the entire measurement. The data were exported with ExpeData software (Sable Systems) and EE was analyzed using ANCOVA with BW as a covariate by a web-based CalR tool80.

These data suggest that adipocyte-specific Rala deletion improved glucose homeostasis partially through reduced hepatic glucose production. The process by which the cycle of reproduction is achieved by only one parent is called asexual reproduction. Examples include binary fission, budding, fragmentation, and parthenogenesis. The process of binary fission is found in bacteria wherein a single bacterium tends to divide into two cells. In budding, very small organs are formed in the bodies of the parent and thus after some time, they tend to break and thus finally grow into two individuals. This type of asexual reproduction is found in yeasts and some other hydra animals.

White adipocyte-specific Rala deletion protects mice from high-fat-diet-induced obesity

Thus, DNA cloning is an important cellular process in asexual reproduction. The process of fragmentation is very vital in biology for asexual reproduction. As described earlier, this is the form of reproduction in which small organs or parts of the body of the parent individual get separated and finally grows into a completely mature organism. Let us take an example of Planaria, one of the many flatworms, belonging to the class of Rhabditophora and phylum Platyhelminthes. See Figure 3 for the depiction of fragmentation and the step involved during fragmentation in Planaria. Fragmentation is a critical issue that can significantly impact the performance of an operating system.

RNA extractions from primary mature inguinal and epididymal adipocytes were performed using TRIzol (Life technologies) and PureLink RNA mini kit (Life Technologies), according to the manufacturer’s instructions. Biological triplicates of isolated 500 ng RNA were used to prepare sequencing libraries using the TruSeq RNA Sample Preparation kit v.2 (Illumina), according to the manufacturer’s protocol. Libraries were validated using a 2100 BioAnalyzer (Agilent), then normalized and pooled for sequencing using bar-coded multiplexing at a 90-bp single-end read length on an Illumina HiSeq 4000.

A more fragmented storage device’s performance will degrade with time, necessitating the requirement for time-consuming defragmentation operations. On the other hand, reducing the MTU too much can have negative consequences, such as reducing the overall capacity of the network and increasing the overhead caused by transmitting smaller packets. As a result, network administrators must perform a balancing act where they consider the trade-offs of adjusting the MTU against the potential for IP fragmentation.

Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes

To determine whether RalA influences CL-induced PKA activation or cAMP breakdown, we measured cAMP production and phosphorylation of hormone-sensitive lipase (HSL) in adipocytes. There were no differences in cAMP production between WT and KO primary adipocytes after 5 min of CL stimulation (Extended Data Fig. 6l). Similarly, HSL S660 phosphorylation was identical in WT and KO adipocytes (Extended Data Fig. 6m,n). Thus, RalA specifically modulates Drp1 S637 phosphorylation downstream of PKA activation across multiple adipocyte cell lines of both murine and human origin. To explore further whether RalA plays a role in glucose homeostasis and energy metabolism, we generated adipocyte-specific Rala knockout (KO) (RalaAKO) mice by crossing Rala-floxed mice with adiponectin-Cre transgenic mice.

On the other hand, triggering Drp1 S637 phosphorylation has been suggested to increase the uncoupling capacity of FFA in brown adipocytes65. In line with this observation, increased S637 phosphorylation was found in BAT after cold exposure66. Administration of a Drp1 inhibitor acutely improved muscle insulin sensitivity and systemic glucose tolerance67,68; however, the impact of modulating Drp1 levels and phosphorylation states is complicated and varies between tissues.

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